Methods of treating psoriasis using il-17 antagonists

ABSTRACT

The disclosure relates to novel regimens for treating psoriasis, which employ a therapeutically effective amount of an IL-17 antagonist, e.g., an IL-17 binding molecule, e.g., an IL-17 antibody, such as the secukinumab antibody, or an IL-17 receptor binding molecule, e.g., an IL-17 receptor antibody.

This disclosure claims priority to U.S. Provisional Patent ApplicationNo. 61/391,388, filed Oct. 8, 2010, the disclosure of which isincorporated by reference herein in its entirety.

TECHNICAL FIELD

The disclosure relates to novel regimens for treating psoriasis, whichemploy a therapeutically effective amount of an IL-17 antagonist, e.g.,an IL-17 binding molecule, e.g., an IL-17 antibody, such as the AIN457antibody (which is also known as “secukinumab”).

BACKGROUND OF THE DISCLOSURE

Psoriasis is a chronic relapsing disease of the skin characterized byvariable clinical features. Plaque (also called plaque-type or chronicplaque) psoriasis, which presents with erythrosquamous plaques, is themost frequent clinical presentation and, therefore, also calledpsoriasis vulgaris. Accumulating evidence indicates that psoriasis is amulti-factorial disorder caused by the concerted action of multipledisease genes in a single individual, triggered by environmentalfactors. It has been speculated that this could be due to the effects ofa chronic inflammatory condition. Regardless of the origin, oncepsoriasis has appeared as a localized disease, it persists throughoutlife, manifesting at often unpredictable intervals.

Traditional approaches for treating moderate to severe psoriasis includetopical therapy, phototherapy (UVB, PUVA), and small molecule systemictherapy, namely methotrexate and cyclosporin. Safety, largely related tocumulative kidney and liver toxicity, is a major concern duringlong-term psoriasis treatment using cyclosporine and methotrexate, andrequires frequent monitoring. McClure et al. (2001) Drug Safety25:913-27. To reduce safety concerns, physicians have developedstrategies such as combination, rotation, sequential and intermittentapproaches in order to avoid cumulative organ toxicity (or, in the caseof phototherapy, potential malignancy). Van de Kerkhoff et al. (2001)Clin. Exp. Dermatol 26:356-61. In general, when rotating to a newtherapy, a first drug is gradually tapered while a next drug (or nexttherapy) is introduced. In some cases, after a first drug is tapered, apatient may be untreated until mild symptoms appear, at which timephototherapy or topical therapy is employed until symptoms are no longertolerable, and a second drug is then introduced. Using this method,repeat treatment with a first drug may be delayed as long as possible(e.g., years). However, rebound can occur during cyclical therapies,e.g., in response to cyclosporin. Moreover, even during a “holiday” fromthe primary drug, the patient is typically undergoing psoriasistreatment using phototherapy or topical therapy.

Biologics appeared to present a solution to the unwieldy, dangerous, andinconvenient traditional systemic psoriasis treatment regimens. Giventhat biologics should have no organ toxicity, prolonged use thereofwould be expected to be safe, making life-long treatment feasible.Unfortunately, adverse events have occurred to varying extent duringchronic biologic treatment of psoriasis, most notably the reactivationof latent tuberculosis infections and the induction (or exacerbation of)demyelinating conditions due to TNF-alpha antagonism. Ferrandiz et al.(2010) Clinics in Dermatology 28:81-87. Other adverse events includethrombocytopenia, psoriasis-related adverse events (e.g., papulareruptions and inflammatory flares), liver toxicity, lymphopenia, andcardiovascular complications (including congestive heart failure or itsworsening). Ferrandiz et al.; Sullivan and Preda (2009) Aust. Prescr.32:14-18; Korkina et al. (2010) Drugs of Today 46:119-36. As a result,some clinicians have modified biological treatment regimens in theirpractice, i.e., by discontinuing and reinitiating therapy. However,concerns about intermittent biologic therapy, which include rebound,immunogenicity upon retreatment, and decreased response compared to thatachieved during a first regimen (which occurs during infliximab,adalimumab and etanercept retreatment), suggest that some biologictherapies are best used in a continuous rather than on-demand setting.Ferrandiz et al.; Sullivan and Preda; Menter et al. (2008) J. Am. Acad.Dermatol 58:826-850; Gelfand et al. (2008) Value in Health 11:400-407;Menter et al. (2007) Am Acad Dermatol. 56(1):31.

The financial burden of long term continuous biological treatment istremendous. There are also concerns that the long term usage ofbiologics, especially chronic TNF-alpha antagonists, might result inmalignancies and other serious disorders. Accordingly, new psoriasistreatment regimens, which avoid the dangers of traditional continuoussystemic therapy (i.e., inconvenient rotational therapy, side effects,organ toxicity) and continuous biologic therapy (i.e., infection,potential malignancy, financial burden, unknown long-term side effects),as well as the drawbacks of intermittent therapy (i.e., rebound,decreased retreatment response) are needed. Herein are disclosed novelregimens for the treatment of psoriasis, which overcome the obstaclesencountered during continuous systemic therapy (both small molecule orbiological) and intermittent biologic therapy.

SUMMARY OF THE DISCLOSURE

IL-17A is the central lymphokine of a subset of inflammatory T cells,the Th17 cells which, in several animal models, are pivotal in severalautoimmune and inflammatory processes. IL-17A is mainly produced bymemory effector CD4+ and CD8+T lymphocytes. IL-17A is being recognizedas one of the principal pro-inflammatory cytokines in immune mediatedinflammatory diseases. Neutralization of IL-17A may be used to treat theunderlying pathophysiology of immune mediated disease, and as aconsequence provide relief of symptoms.

The psoriasis treatment regimens of the disclosure employ atherapeutically effective amount of an IL-17 antagonist, e.g., an IL-17binding molecule, e.g., an IL-17 antibody, such as the AIN457 antibody(secukinumab). Secukinumab, disclosed in WO 2006/013107 (also publishedas US20090280131, which is hereby incorporated by reference in itsentirety), is a recombinant high-affinity fully human monoclonalanti-human Interleukin-17A antibody of the IgG1/κ-class. Secukinumabbinds to human IL-17A and neutralizes the bioactivity of this cytokine.Secukinumab has a very high affinity for IL-17, i.e., a K_(D) of about100-200 pM and an IC₅₀ of about 0.4 nM for in vitro neutralization ofthe biological activity of 0.67 nM human IL-17A. Thus, secukinumabneutralizes antigen at a molar ratio of about 1:1. This high bindingaffinity makes secukinumab particularly suitable for therapeuticapplications. Furthermore, secukinumab has a very long half life, i.e.,about 4 weeks (i.e., about 30 days), which allows for prolonged periodsbetween administration, an exceptional property when treating chroniclife-long disorders, such as psoriasis. Due to the long half-life, highaffinity and fast onset of action of secukinumab, it is possible totreat psoriasis using relatively low doses of secukinumab administeredat infrequent intervals.

It is an object of the disclosure to provide novel treatment regimensfor psoriasis, which employ induction and/or maintenance regimens usingtherapeutically effective amounts of an IL-17 antagonist, e.g., an IL-17binding molecule, e.g., IL-17 antibody, such as secukinumab. It is ananother object of the disclosure to provide novel methods of treatingpsoriasis in patients at start of relapse (SoR), which employ atherapeutically effective amount of an IL-17 antagonist, e.g., an IL-17binding molecule, e.g., IL-17 antibody, such as secukinumab. Treatmentat SoR allows an individualized approach to psoriasis therapy andprovides effective relief, while employing the lowest possible dose ofdrug.

Accordingly, disclosed herein are methods of treating psoriasis,comprising: a) administering an IL-17 antagonist, e.g., an IL-17 bindingmolecule, to a patient in need thereof during an induction regimen; andb) thereafter administering the IL-17 antagonist, e.g., IL-17 bindingmolecule, to the patient during a maintenance regimen. The maintenanceregimen may employ continuous (e.g., monthly treatment) or intermittentdosing (e.g., treatment at SoR).

Disclosed herein are methods of treating psoriasis, comprising: a)administering an IL-17 antagonist, e.g., IL-17 binding molecule to apatient in need thereof during an induction regimen, wherein theinduction regimen comprises a loading regimen, wherein the loadingregimen comprises administering the patient five doses of about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) of the IL-17antagonist, e.g., IL-17 binding molecule, each of the five doses beingdelivered weekly, beginning on week zero; and b) thereafter,administering the IL-17 antagonist, e.g., IL-17 binding molecule to thepatient during a maintenance regimen.

Disclosed herein are IL-17 antagonists, e.g., IL-17 binding moleculesfor use in treating psoriasis, characterized in that at least one doseof the IL-17 antagonist, e.g., IL-17 binding molecule is administered toa patient at start of relapse from a prior treatment with the IL-17antagonist, e.g., IL-17 binding molecule. Also disclosed herein aremethods of treating psoriasis, comprising: a) identifying a patient atstart of relapse from a prior psoriasis treatment employing an IL-17antagonist, e.g., IL-17 binding molecule; and b) administering to thepatient at least one dose of the IL-17 antagonist, e.g., IL-17 bindingmolecule.

Disclosed herein are methods of treating psoriasis, comprising: a)administering a patient in need thereof five doses of about 75 mg-about300 mg (e.g., about 150 mg-about 300 mg) of an IL-17 antagonist, e.g.,IL-17 binding molecule, each of the five doses being delivered weekly,beginning on week zero; b) administering the patient about 75 mg-about300 mg (e.g., about 150 mg-about 300 mg) the IL-17 binding moleculeduring week eight; c) administering the patient at least one dose ofabout 75 mg-about 300 mg (e.g., about 150 mg-about 300 mg) the IL-17antagonist, e.g., IL-17 binding molecule at start of relapse; and d)repeating step c) at each additional start of relapse.

Disclosed herein are therapeutic regimens for treating psoriasis,comprising: a) administering an IL-17 antagonist, e.g., IL-17 bindingmolecule to a patient in need thereof during an induction regimencomprising: i. administering about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 binding moleculeto the patient weekly for five weeks, wherein the first dose of theIL-17 antagonist, e.g., IL-17 binding molecule is administered duringweek zero; and ii. thereafter administering about 75 mg-about 300 mg(e.g., about 150 mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17binding molecule to the patient during week eight; and b) administeringthe IL-17 antagonist, e.g., IL-17 binding molecule to the patient duringa maintenance regimen comprising: i. administering about 75 mg-about 300mg (e.g., about 150 mg-about 300 mg) of the IL-17 binding molecule tothe patient each month, every two months or every three months; or ii.administering at least one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 bindingmolecule to the patient at start of relapse.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 antagonist, e.g., IL-17binding molecule is to be administered: a) during an induction regimen,wherein the induction regimen comprises a loading regimen, wherein theloading regimen comprises administering five doses of about 75 mg-about300 mg (e.g., about 150 mg-about 300 mg) of the IL-17 antagonist, e.g.,IL-17 binding molecule, each of the five doses being delivered weekly,beginning on week zero; and b) thereafter, during a maintenance regimen.

Disclosed herein are IL-17 antagonists, e.g., IL-17 binding moleculesfor use in treating psoriasis, characterized in that the IL-17antagonist, e.g., IL-17 binding molecule is: a) to be administered to apatient in need thereof as five doses of about 75 mg-about 300 mg (e.g.,about 150 mg-about 300 mg), each of the five doses being deliveredweekly, beginning on week zero; b) thereafter to be administered to thepatient during week eight in an amount of about 75 mg-about 300 mg(e.g., about 150 mg-about 300 mg); c) thereafter to be administered tothe patient as at least one dose of about 75 mg-about 300 mg (e.g.,about 150 mg-about 300 mg) at start of relapse; and d) thereafter to beadministered to the patient at start of each additional relapse as atleast one dose of about 75 mg-about 300 mg (e.g., about 150 mg-about 300mg).

Disclosed herein are IL-17 antagonists, e.g., IL-17 binding moleculesfor use in treating psoriasis, characterized in that the IL-17antagonist, e.g., IL-17 binding molecule is: a) to be administered to apatient in need thereof during an induction regimen comprising: i. theIL-17 antagonist, e.g., IL-17 binding molecule is to be administered tothe patient at a dose of about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) weekly for five weeks, wherein the first dose of theIL-17 antagonist, e.g., IL-17 binding molecule is to be administeredduring week zero; and ii. thereafter the IL-17 antagonist, e.g., IL-17binding molecule is to be administered to the patient at a dose of about75 mg-about 300 mg (e.g., about 150 mg-about 300 mg) during week eight;and b) to be administered to the patient during a maintenance regimencomprising: i. the IL-17 antagonist, e.g., IL-17 binding molecule is tobe administered to the patient at a dose of about 75 mg-about 300 mg(e.g., about 150 mg-about 300 mg) each month, every two months or everythree months; or ii. the IL-17 antagonist, e.g., IL-17 binding moleculeis to be administered to the patient as at least one dose of about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) of the IL-17antagonist, e.g., IL-17 binding molecule at start of relapse.

Disclosed herein are uses of IL-17 antagonists, e.g., IL-17 bindingmolecules for the manufacture of a medicament for treating psoriasis,characterized in that the IL-17 antagonist, e.g., IL-17 binding moleculeis to be administered to a patient at start of relapse from a priortreatment with the IL-17 antagonist, e.g., IL-17 binding molecule.

Disclosed herein are IL-17 antagonists, e.g., IL-17 binding moleculesfor use in treating psoriasis in a patient, wherein said patient is tobe identified at start of relapse from a prior treatment with the IL-17antagonist, e.g., IL-17 binding molecule and wherein said patient is tobe administered at least one dose of the IL-17 antagonist, e.g., IL-17binding molecule.

Disclosed herein are pharmaceutical compositions for treating psoriasis,comprising as an active ingredient and the IL-17 antagonist, e.g., IL-17binding molecule, wherein the IL-17 antagonist, e.g., IL-17 bindingmolecule is to be administered to a patient at start of relapse from aprior treatment with the IL-17 antagonist, e.g., IL-17 binding molecule.

Disclosed herein are methods of treating psoriasis, comprising: a)administering a patient in need thereof five weekly doses of about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) of an IL-17antagonist, e.g., IL-17 binding molecule; and b) thereafteradministering: i) about 75 mg-about 300 mg (e.g., about 150 mg-about 300mg) of the IL-17 antagonist, e.g., IL-17 binding molecule to the patientmonthly or ii) one dose of about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 binding moleculeto the patient about one month following step a) and thereafteradministering at least one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 bindingmolecule to the patient at start of relapse.

Disclosed herein are therapeutic regimens for treating psoriasis,comprising: a) administering a patient in need thereof five weekly dosesof about 75 mg-about 300 mg (e.g., about 150 mg-about 300 mg) of anIL-17 antagonist, e.g., IL-17 binding molecule; and b) thereafteradministering: i) about 75 mg-about 300 mg (e.g., about 150 mg-about 300mg) of the IL-17 antagonist, e.g., IL-17 binding molecule to the patientmonthly or ii) one dose of about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 binding moleculeto the patient about one month following step a) and thereafteradministering at least one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 bindingmolecule to the patient at start of relapse.

Disclosed herein are methods of treating psoriasis, comprising: a)administering an IL-17 antagonist, e.g., IL-17 binding molecule to apatient in need thereof during an induction regimen, wherein theinduction regimen comprises a loading regimen that provides a meanmaximum plasma concentration (C_(max)) of the IL-17 antagonist, e.g.,IL-17 binding molecule of about 52 μg/ml-about 104 μg/ml; and b)thereafter administering the IL-17 antagonist, e.g., IL-17 bindingmolecule to the patient during a maintenance regimen that provides anaverage steady-state trough level of the IL-17 antagonist, e.g., IL-17binding molecule between about 5 μg/ml-about 70 μg/ml.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered to the patient during an induction regimen, wherein theinduction regimen comprises a loading regimen that provides a meanmaximum plasma concentration (C_(max)) of the IL-17 binding molecule ofabout 52 μg/ml-about 104 μg/ml; and b) thereafter, is to be administeredto the patient during a maintenance regimen that provides an averagesteady-state trough level of the IL-17 binding molecule between about 5μg/ml-about 70 μg/ml.

Disclosed herein are methods of treating psoriasis, comprising: a)administering an IL-17 antagonist, e.g., IL-17 binding molecule to apatient in need thereof during an induction regimen, wherein theinduction regimen comprises a loading regimen that provides a meantrough level one month after the fourth dose of about 29.2 μg/ml; and b)thereafter administering the IL-17 antagonist, e.g., IL-17 bindingmolecule to the patient during a maintenance regimen that provides anaverage steady-state trough level of the IL-17 antagonist, e.g., IL-17binding molecule of about 15 μg/ml.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered to the patient during an induction regimen, wherein theinduction regimen comprises a loading regimen that provides a meantrough level one month after the fourth dose of about 29.2 μg/ml; and b)thereafter, is to be administered to the patient during a maintenanceregimen that provides an average steady-state trough level of the IL-17binding molecule of about 15 μg/ml.

In some of the above mentioned methods, therapeutic regimens, kits,uses, and pharmaceutical compositions, the prior treatment with theIL-17 antagonist, e.g., IL-17 binding molecule comprises an inductionregimen. In further embodiments, the induction regimen comprises aloading regimen. In some embodiments, the loading regimen comprisesadministering the patient five doses of about 75 mg-about 300 mg (e.g.,about 150 mg-about 300 mg) of the IL-17 antagonist, e.g., IL-17 bindingmolecule, each of the five doses being delivered weekly, beginning onweek zero. In some embodiments, the five doses are each about 75 mg,about 150 mg or about 300 mg. In some embodiments, five doses of about150 mg are administered to the patient if the patient weighs less than90 kg and five doses of about 300 mg are administered to the patient ifthe patient weighs more than or equal to 90 kg. In some embodiments, theinduction regimen further comprises administering the patient about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) the IL-17 antagonist,e.g., IL-17 binding molecule during week eight. In some embodiments, theprior treatment with the IL-17 antagonist, e.g., IL-17 binding moleculecomprises administering to the patient at least one dose of the IL-17antagonist, e.g., IL-17 binding molecule at start of relapse. In some ofthe above mentioned methods, therapeutic regimens, kits, uses, andpharmaceutical compositions, start of relapse is defined as the loss of20% of the maximum PASI response achieved at any time before the visitat which the assessment of start of relapse is made and loss of PASI 75.In some of the above mentioned methods, therapeutic regimens, kits,uses, and pharmaceutical compositions, the psoriasis is chronicplaque-type psoriasis.

In some of the above mentioned methods, therapeutic regimens,combinations, combination therapies, kits, uses, and pharmaceuticalcompositions, the IL-17 antagonist, e.g., IL-17 binding molecule isselected from the group consisting of:

a) secukinumab;

b) an IL-17 antibody that binds to an epitope of IL-17 comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129;

c) an IL-17 antibody that binds to an epitope of IL-17 comprising Tyr43,Tyr44, Arg46, Ala79, Asp80;

d) an IL-17 antibody that binds to an epitope of an IL-17 homodimerhaving two mature IL-17 protein chains, said epitope comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the otherchain;

e) an IL-17 antibody that binds to an epitope of an IL-17 homodimerhaving two mature IL-17 protein chains, said epitope comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the otherchain, wherein the IL-17 binding molecule has a K_(D) of about 100-200pM, and wherein the IL-17 binding molecule has an in vivo half-life ofabout 4 weeks; and

f) an IL-17 antibody that comprises an antibody selected from the groupconsisting of:

-   -   i) an immunoglobulin heavy chain variable domain (V_(H))        comprising the amino acid sequence set forth as SEQ ID NO:8;    -   ii) an immunoglobulin light chain variable domain (V_(L))        comprising the amino acid sequence set forth as SEQ ID NO:10;    -   iii) an immunoglobulin V_(H) domain comprising the amino acid        sequence set forth as SEQ ID NO:8 and an immunoglobulin V_(L)        domain comprising the amino acid sequence set forth as SEQ ID        NO:10;    -   iv) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3;    -   v) an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;    -   vi) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID        NO:13;    -   vii) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3        and an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;        and    -   viii) an immunoglobulin V_(H) domain comprising the        hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12        and SEQ ID NO:13 and an immunoglobulin V_(L) domain comprising        the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5        and SEQ ID NO:6.

In the above mentioned methods, therapeutic regimens, kits, uses, andpharmaceutical compositions, a preferred embodiment employs a humanantibody to IL-17, e.g., most preferably secukinumab.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that rebound is not observed in secukinumab-treatedpatients within 8 weeks after dosing. The figure shows individualpatient profiles from study CAIN457A2212. All patients in each group areshown. Baseline PASI is shown as 100% for all patients. A PASI 75response is achieved if the curve reaches 25% on the Y-axis. A reboundwould have been observed if 125% on the Y-Axis (marked with a horizontalgray line) would have been reached within 8 weeks after last study drugadministration. Note that the time point of eight weeks after last studydrug administration (marked in the figure with a vertical gray line) isat Week 8 for the groups “1×3 mg/kg” and “1×10 m/kg”, but at Week 12 forthe “3×10 mg/kg” group; the “placebo” group did not receive any activetreatment.

FIG. 2 shows the study design for clinical trial CAIN457A2211.

FIG. 3 shows PASI75 response rates in study CAIN457A2211 during the 12week induction phase, following different treatment regimens of 150 mgs.c. secukinumab. The arrows indicate the time points of secukinumabadministration. No secukinumab was administered in the placebo arm.

FIG. 4 Study CAIN457A2211: PASI 75 achievement response rates by patientvisit treatment week (subgroup of subjects randomized to the maintenanceperiod). By definition, the PASI 75 response rate at Week 13 was 100%,as only patients with a PASI 75 achievement were re-randomized into thedouble-blind maintenance treatment period of the study. Patients in the“Fixed Interval” group received 150 mg of secukinumab at Week 13 and atWeek 25. Patients in the “Start of Relapse” group did not receivesecukinumab at Week 13; the received 150 mg of secukinumab at Weeks 17,21, 25, and 29 ONLY if they suffered from a start of relapse at therespective time point. 4A shows results for both the “Fixed Interval”and the “Start of Relapse” groups. 4B shows only the results of the“Fixed Interval” group. The difference in response rate compared to Week13 (100% by definition) is given for Weeks 17, 21, and 25. The timepoints of secukinumab (AIN457) administration are indicated.

FIG. 5 shows the observed cumulative probability to experience “Start ofRelapse” in “individualized treatment” maintenance in studyCAIN457A2211. In the figure the percentage of subjects with start ofrelapse (y-axis) is plotted versus time in weeks since last secukinumabinjection in the induction period. Patients were treated with one of thethree secukinumab induction regimes (“Single”, “Monthly”, and “Early”)during the first twelve weeks. As a result, the time since lastsecukinumab administration differs within this group.

FIG. 6 shows the study design for clinical trial CAIN457A2220.

FIG. 7 shows PASI 75 response rates from in study CAIN457A2220 (12weeks). Subjects with “monthly” treatment received injections ofsecukinumab at Weeks 0, 4, and 8. Subjects in the “25 mg single” armreceived secukinumab at Week 0 only. Placebo patients did not receivesecukinumab injections.

FIG. 8 shows simulated PK plasma concentration profiles of secukinumabfor the regimens implemented in phase III (subcutaneous), as well as forregimens in studies CAIN457A2212 (intravenous route of administration)and CAIN457A2211 (subcutaneous). All simulated profiles are for typicalpatients, assuming a body weight of 90.9 kg (based on the typical bodyweight observed in secukinumab in psoriasis studies).”

FIG. 9 shows simulated PASI 75 induction and maintenance response ratesfor doses 75 mg. 150 mg and 300 mg for a treatment duration of 200 days.After induction treatment (Weeks 0, 1, 2, 3, 4, and 8), doses are givenat Week 12 and every four weeks thereafter.

FIG. 10 shows simulated PASI 75 response rates for different fixedtreatment intervals. On the basis of one of the doses for phase III (150mg), the impact of different fixed treatment intervals (4, 8, and 12weeks) is simulated for the treatment duration of 365 days. Inductiontreatment is identical for all three groups, and the first dose inmaintenance is given on day 84 (=Week 12) in all groups.

FIG. 11 shows the study design for clinical trial CAIN457A2304.

DETAILED DESCRIPTION OF THE DISCLOSURE

Various aspects of the disclosure are described in further detail in thefollowing subsections. All patents, published patent applications,publications, references and other material referred to herein areincorporated by reference herein in their entirety.

The term “comprising” encompasses “including” as well as “consisting,”e.g., a composition “comprising” X may consist exclusively of X or mayinclude something additional, e.g., X+Y.

The term “about” in relation to a numerical value x means+/−10%, unlessthe cotext dictates otherwise.

The word “substantially” does not exclude “completely” e.g., acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the disclosure.

“IL-17 antagonist” as used herein refers to a molecule capable ofantagonizing (e.g., reducing, inhibiting, decreasing, delaying) IL-17function, expression and/or signalling (e.g., by blocking the binding ofIL-17 to the IL-17 receptor). Non-limiting examples of IL-17 antagonistsinclude IL-17 binding molecules and IL-17 receptor binding molecules. Insome embodiments of the disclosed methods, regimens, kits, processes,uses and compositions, an IL-17 antagonist is employed.

By “IL-17 binding molecule” is meant any molecule capable of binding tothe human IL-17 antigen either alone or associated with other molecules.The binding reaction may be shown by standard methods (qualitativeassays) including, for example, a binding assay, competition assay or abioassay for determining the inhibition of IL-17 binding to its receptoror any kind of binding assays, with reference to a negative control testin which an antibody of unrelated specificity but of the same isotype,e.g. an anti-CD25 antibody, is used. Non-limiting examples of IL-17binding molecules include small molecules, IL-17 receptor decoys, andantibodies as produced by B-cells or hybridomas and chimeric,CDR-grafted or human antibodies or any fragment thereof, e.g., F(ab′)₂and Fab fragments, as well as single chain or single domain antibodies.Preferably the IL-17 binding molecule antagonizes (e.g., reduces,inhibits, decreases, delays) IL-17 function, expression and/orsignalling. In some embodiments of the disclosed methods, regimens,kits, processes, uses and compositions, an IL-17 binding molecule isemployed.

By “IL-17 receptor binding molecule” is meant any molecule capable ofbinding to the human IL-17 receptor either alone or associated withother molecules. The binding reaction may be shown by standard methods(qualitative assays) including, for example, a binding assay,competition assay or a bioassay for determining the inhibition of IL-17receptor binding to IL-17 or any kind of binding assays, with referenceto a negative control test in which an antibody of unrelated specificitybut of the same isotype, e.g. an anti-CD25 antibody, is used.Non-limiting examples of IL-17 receptor binding molecules include smallmolecules, IL-17 decoys, and antibodies to the IL-17 receptor asproduced by B-cells or hybridomas and chimeric, CDR-grafted or humanantibodies or any fragment thereof, e.g., F(ab′)2 and Fab fragments, aswell as single chain or single domain antibodies. Preferably the IL-17receptor binding molecule antagonizes (e.g., reduces, inhibits,decreases, delays) IL-17 function, expression and/or signalling. In someembodiments of the disclosed methods, regimens, kits, processes, usesand compositions, an IL-17 receptor binding molecule is employed.

The term “antibody” as referred to herein includes whole antibodies andany antigen-binding portion or single chains thereof. A naturallyoccurring “antibody” is a glycoprotein comprising at least two heavy (H)chains and two light (L) chains inter-connected by disulfide bonds. Eachheavy chain is comprised of a heavy chain variable region (abbreviatedherein as V_(H)) and a heavy chain constant region. The heavy chainconstant region is comprised of three domains, CH1, CH2 and CH3. Eachlight chain is comprised of a light chain variable region (abbreviatedherein as V_(L)) and a light chain constant region. The light chainconstant region is comprised of one domain, CL. The V_(H) and V_(L)regions can be further subdivided into regions of hypervariability,termed complementarity determining regions (CDR), interspersed withregions that are more conserved, termed framework regions (FR). EachV_(H) and V_(L) is composed of three CDRs and four FRs arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and lightchains contain a binding domain that interacts with an antigen. Theconstant regions of the antibodies may mediate the binding of theimmunoglobulin to host tissues or factors, including various cells ofthe immune system (e.g., effector cells) and the first component (C1q)of the classical complement system. In some embodiments of the disclosedmethods, regimens, kits, processes, uses and compositions, an antibodyto IL-17 or the IL-17 receptor is employed.

The term “antigen-binding portion” of an antibody as used herein, refersto fragments of an antibody that retain the ability to specifically bindto an antigen (e.g., IL-17). It has been shown that the antigen-bindingfunction of an antibody can be performed by fragments of a full-lengthantibody. Examples of binding fragments encompassed within the term“antigen-binding portion” of an antibody include a Fab fragment, amonovalent fragment consisting of the V_(L), V_(H), CL and CH1 domains;a F(ab)2 fragment, a bivalent fragment comprising two Fab fragmentslinked by a disulfide bridge at the hinge region; a Fd fragmentconsisting of the V_(H) and CH1 domains; a Fv fragment consisting of theV_(L) and V_(H) domains of a single arm of an antibody; a dAb fragment(Ward et al., 1989 Nature 341:544-546), which consists of a V_(H)domain; and an isolated complementarity determining region (CDR).Exemplary antigen binding sites include the CDRs of secukinumab as setforth in SEQ ID NOs:1-6 and 11-13 (Table 5), preferably the heavy chainCDR3. Furthermore, although the two domains of the Fv fragment, V_(L)and V_(H), are coded for by separate genes, they can be joined, usingrecombinant methods, by a synthetic linker that enables them to be madeas a single protein chain in which the V_(L) and V_(H) regions pair toform monovalent molecules (known as single chain Fv (scFv); see, e.g.,Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc.Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are alsointended to be encompassed within the term “antibody”. Single chainantibodies and antigen-binding portions are obtained using conventionaltechniques known to those of skill in the art. In some embodiments ofthe disclosed methods, regimens, kits, processes, uses and compositions,a single chain antibody or an antigen-binding portion of an antibodyagainst IL-17 or the IL-17 receptor is employed.

The term “pharmaceutically acceptable” means a nontoxic material thatdoes not interfere with the effectiveness of the biological activity ofthe active ingredient(s).

An “isolated antibody”, as used herein, refers to an antibody that issubstantially free of other antibodies having different antigenicspecificities (e.g., an isolated antibody that specifically binds IL-17is substantially free of antibodies that specifically bind antigensother than IL-17). An isolated antibody may be substantially free ofother cellular material and/or chemicals. An isolated antibody that“specifically binds” IL-17 may be crossreactive with other antigens,such as IL-17 molecules from other species. In some embodiments of thedisclosed methods, regimens, kits, processes, uses and compositions, theIL-17 binding molecule is an isolated antibody.

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope. Insome embodiments of the disclosed methods, regimens, kits, processes,uses and compositions, the IL-17 binding molecule is a monoclonalantibody.

The term “human antibody”, as used herein, is intended to includeantibodies having variable regions in which both the framework and CDRregions are derived from sequences of human origin. Furthermore, if theantibody contains a constant region, the constant region also is derivedfrom such human sequences, e.g., human germline sequences, or mutatedversions of human germline sequences or antibody containing consensusframework sequences derived from human framework sequences analysis asdescribed in Knappik, et al. (2000. J Mol Biol 296, 57-86). A “humanantibody” need not be produced by a human, human tissue or human cell.The human antibodies of the disclosure may include amino acid residuesnot encoded by human sequences (e.g., mutations introduced by random orsite-specific mutagenesis in vitro or by somatic mutation in vivo).However, the term “human antibody”, as used herein, is not intended toinclude antibodies in which CDR sequences derived from the germline ofanother mammalian species, such as a mouse, have been grafted onto humanframework sequences. In some embodiments of the disclosed methods,regimens, kits, processes, uses and compositions, the IL-17 bindingmolecule is a human antibody.

The term “IL-17” refers to IL-17A, formerly known as CTLA8, and includeswild-type IL-17A from various species (e.g., human, mouse, and monkey),polymorphic variants of IL-17A, and functional equivalents of IL-17A.Functional equivalents of IL-17A according to the present disclosurepreferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, oreven 99% overall sequence identity with a wild-type IL-17A (e.g., humanIL-17A), and substantially retain the ability to induce IL-6 productionby human dermal fibroblasts.

The term “K_(dis)” or “K_(D),” as used herein, is intended to refer tothe dissociation rate of a particular antibody-antigen interaction,which is obtained from the ratio of K_(d) to K_(a) (i.e. K_(d)/K_(a))and is expressed as a molar concentration (M). K_(D) values forantibodies can be determined using methods well established in the art.A method for determining the K_(D) of an antibody is by using surfaceplasmon resonance, or using a biosensor system such as a Biacore®system.

As used herein, the term “affinity” refers to the strength ofinteraction between antibody and antigen at single antigenic sites.Within each antigenic site, the variable region of the antibody “arm”interacts through weak non-covalent forces with antigen at numeroussites; the more interactions, the stronger the affinity. Standard assaysto evaluate the binding affinity of the antibodies toward IL-17 ofvarious species are known in the art, including for example, ELISAs,western blots and RIAs. The binding kinetics (e.g., binding affinity) ofthe antibodies also can be assessed by standard assays known in the art,such as by Biacore analysis. Assays to evaluate the effects of theantibodies on functional properties of IL-17 (e.g., receptor binding,preventing or ameliorating osteolysis) are described in further detailin the Examples.

As used herein, the term “subject” and “patient” includes any human ornonhuman animal. The term “nonhuman animal” includes all vertebrates,e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs,cats, horses, cows, chickens, amphibians, reptiles, etc.

An antibody that “inhibits” one or more of the functional properties ofIL-17 (e.g., biochemical, immunochemical, cellular, physiological orother biological activities, or the like) as determined according tomethodologies known to the art and described herein, will be understoodto relate to a statistically significant decrease in the particularactivity relative to that seen in the absence of the antibody (or when acontrol antibody of irrelevant specificity is present). An antibody thatinhibits IL-17 activity causes a statistically significant decrease,e.g., by at least 10% of the measured parameter, by at least 50%, 80% or90%, and in certain embodiments an antibody of the disclosure mayinhibit greater than 95%, 98% or 99% of IL-17 functional activity.

The term “derivative”, unless otherwise indicated, is used to defineamino acid sequence variants, and covalent modifications of the IL-17binding molecules and IL-17 receptor binding molecules according to thepresent disclosure, e.g., of a specified sequence.

A “functional derivative” includes a molecule having a qualitativebiological activity in common with the disclosed IL-17 binding moleculesand IL-17 receptor binding molecules. A functional derivative includesfragments and peptide analogs of an IL-17 binding molecule or an IL-17receptor binding molecule according to the present disclosure. Fragmentscomprise regions within the sequence of a polypeptide according to thepresent disclosure, e.g., of a specified sequence. Functionalderivatives of the IL-17 binding molecules or IL-17 receptor bindingmolecules disclosed herein preferably comprise V_(H) and/or V_(L)domains that have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, oreven 99% overall sequence identity with the V_(H) and/or V_(L) sequencesof the IL-17 binding molecules and IL-17 receptor binding moleculesdisclosed herein (e.g., the V_(H) and/or V_(L) sequences of Table 5), orcomprise CDRs that have at least about 65%, 75%, 85%, 95%, 96%, 97%,98%, or even 99% overall sequence identity with the CDRs of the IL-17binding molecules (e.g., secukinumab) or IL-17 receptor bindingmolecules disclosed herein (e.g., have 1, 2, or 3 amino acid differencesfrom the CDRs set forth in Table 5), and substantially retain theability to bind the human IL-17 or, e.g., inhibit IL-6 production ofIL-17 induced human dermal fibroblasts. In some embodiments of thedisclosed methods, regimens, kits, processes, uses and compositions,functional derivatives of the IL-17 binding molecules and IL-17 receptorbinding molecules disclosed herein are employed.

“Inhibit IL-6” as used herein refers to the ability of an IL-17 bindingmolecule to decrease IL-6 production from primary human dermalfibroblasts. The production of IL-6 in primary human (dermal)fibroblasts is dependent on IL-17 (Hwang S Y et al., (2004) ArthritisRes Ther; 6:R120-128. In short, human dermal fibroblasts are stimulatedwith recombinant IL-17 in the presence of various concentrations of anIL-17 binding molecule or human IL-17 receptor with Fc part. Thechimeric anti-CD25 antibody Simulect® (basiliximab) may be convenientlyused as a negative control. Supernatant is taken after 16 h stimulationand assayed for IL-6 by ELISA. An IL-17 binding molecule typically hasan IC₅₀ for inhibition of IL-6 production (in the presence 1 nM humanIL-17) of about 50 nM or less (e.g., from about 0.01 to about 50 nM)when tested as above, i.e., said inhibitory activity being measured onIL-6 production induced by hu-IL-17 in human dermal fibroblasts. In someembodiments of the disclosed methods, regimens, kits, processes, usesand compositions, IL-17 binding molecules and functional derivativesthereof have an IC₅₀ for inhibition of IL-6 production as defined aboveof about 20 nM or less, more preferably of about 10 nM or less, morepreferably of about 5 nM or less, more preferably of about 2 nM or less,more preferably of about 1 nM or less.

The term “covalent modification” includes modifications of a polypeptideaccording to the present disclosure, e.g., of a specified sequence; or afragment thereof with an organic proteinaceous or non-proteinaceousderivatizing agent, fusions to heterologous polypeptide sequences, andpost-translational modifications. Covalent modified polypeptides, e.g.,of a specified sequence, still have the ability to bind the human IL-17or, e.g., inhibit IL-6 production of IL-17 induced human dermalfibroblasts by crosslinking. Covalent modifications are traditionallyintroduced by reacting targeted amino acid residues with an organicderivatizing agent that is capable of reacting with selected sides orterminal residues, or by harnessing mechanisms of post-translationalmodifications that function in selected recombinant host cells. Certainpost-translational modifications are the result of the action ofrecombinant host cells on the expressed polypeptide. Glutaminyl andasparaginyl residues are frequently post-translationally deamidated tothe corresponding glutamyl and aspartyl residues. Alternatively, theseresidues are deaminated under mildly acidic conditions. Otherpost-translational modifications include hydroxylation of proline andlysine, phosphorylation of hydroxyl groups of seryl, tyrosine orthreonyl residues, methylation of the α-amino groups of lysine,arginine, and histidine side chains, see, e.g., T. E. Creighton,Proteins: Structure and Molecular Properties, W. H. Freeman & Co., SanFrancisco, pp. 79-86 (1983). Covalent modifications, e.g., includefusion proteins comprising a polypeptide according to the presentdisclosure, e.g., of a specified sequence and their amino acid sequencevariants, such as immunoadhesins, and N-terminal fusions to heterologoussignal sequences. A common example of a non-naturally occurring covalentmodification is pegylation. In some embodiments of the disclosedmethods, regimens, kits, processes, uses and compositions, the IL-17binding molecules or IL-17 receptor binding molecules disclosed hereinare covalently modified.

The phrase “substantially identical” means that the relevant amino acidor nucleotide sequence (e.g., CDR(s), V_(H), or V_(L) domain) will beidentical to or have insubstantial differences (e.g., through conservedamino acid substitutions) in comparison to a particular referencesequence. Insubstantial differences include minor amino acid changes,such as 1 or 2 substitutions in a 5 amino acid sequence of a specifiedregion. In the case of antibodies, the second antibody has the samespecificity and has at least 50% of the affinity of the same. Sequencessubstantially identical (e.g., at least about 85% sequence identity) tothe sequences disclosed herein are also part of this application. Insome embodiments, the sequence identity can be about 90% or greater,e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher.

“Identity” with respect to a native polypeptide and its functionalderivative is defined herein as the percentage of amino acid residues inthe candidate sequence that are identical with the residues of acorresponding native polypeptide, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent identity,and not considering any conservative substitutions as part of thesequence identity. Neither N- or C-terminal extensions nor insertionsshall be construed as reducing identity. Methods and computer programsfor the alignment are well known. The percent identity can be determinedby standard alignment algorithms, for example, the Basic Local AlignmentSearch Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol.,215: 403 410); the algorithm of Needleman et al. ((1970) J. Mol. Biol.,48: 444 453); or the algorithm of Meyers et al. ((1988) Comput. Appl.Biosci., 4: 11 17). A set of parameters may be the Blosum 62 scoringmatrix with a gap penalty of 12, a gap extend penalty of 4, and aframeshift gap penalty of 5. The percent identity between two amino acidor nucleotide sequences can also be determined using the algorithm of E.Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has beenincorporated into the ALIGN program (version 2.0), using a PAM120 weightresidue table, a gap length penalty of 12 and a gap penalty of 4.

“Amino acid(s)” refer to all naturally occurring L-a-amino acids, e.g.,and include D-amino acids. The amino acids are identified by either thewell known single-letter or three-letter designations.

The term “amino acid sequence variant” refers to molecules with somedifferences in their amino acid sequences as compared to the sequencesaccording to the present disclosure. Amino acid sequence variants of apolypeptide according to the present disclosure, e.g., of a specifiedsequence, still have the ability to bind the human IL-17 or, e.g.,inhibit IL-6 production of IL-17 induced human dermal fibroblasts.Substitutional variants are those that have at least one amino acidresidue removed and a different amino acid inserted in its place at thesame position in a polypeptide according to the present disclosure,e.g., of a specified sequence. These substitutions may be single, whereonly one amino acid in the molecule has been substituted, or they may bemultiple, where two or more amino acids have been substituted in thesame molecule. Insertional variants are those with one or more aminoacids inserted immediately adjacent to an amino acid at a particularposition in a polypeptide according to the present disclosure, e.g., ofa specified sequence. Immediately adjacent to an amino acid meansconnected to either the α-carboxy or a-amino functional group of theamino acid. Deletional variants are those with one or more amino acidsin a polypeptide according to the present disclosure, e.g., of aspecified sequence, removed. Ordinarily, deletional variants will haveone or two amino acids deleted in a particular region of the molecule.

As used herein, a “therapeutically effective amount” refers to an amountof an IL-17 antagonist (e.g. a., an IL-17 binding molecule (e.g., anIL-17 antibody, e.g., secukinumab) or IL-17 receptor binding molecule(e.g., an IL-17 receptor antibody)) that is effective, upon single ormultiple dose administration to a subject (such as a human patient) attreating, preventing, curing, delaying, reducing the severity of,ameliorating at least one symptom of a disorder or recurring disorder,or prolonging the survival of the subject beyond that expected in theabsence of such treatment. When applied to an individual activeingredient (e.g., an IL-17 binding molecule) administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially orsimultaneously.

As used herein, the term “psoriasis” includes plaque-type, guttate,inverse, pustular, and erythrodermic psoriasis. A preferred type ofpsoriasis to be treated with the methods, regimens, combinations, kitsand compositions disclosed herein, is plaque-type psoriasis.

The terms “treatment” or “treat” refer to both prophylactic orpreventative treatment as well as curative or disease modifyingtreatment, including treatment of patient at risk of contracting thedisease or suspected to have contracted the disease as well as patientswho are ill or have been diagnosed as suffering from a disease ormedical condition, and includes suppression of clinical relapse. Thetreatment may be administered to a subject having a medical disorder orwho ultimately may acquire the disorder, in order to prevent, cure,delay the onset of, reduce the severity of, or ameliorate one or moresymptoms of a disorder or recurring disorder, or in order to prolong thesurvival of a subject beyond that expected in the absence of suchtreatment.

The following definitions are used according to Committee for medicinalproducts for human use (CHMP), European Medicines Agency for theEvaluation of Medicines for Human Use. (2004) Guideline on clinicalinvestigation of medicinal products indicated for the treatment ofpsoriasis. CHMP/EWP/2454/02 corr document. London, UK:

-   -   Treatment response (responder): Patients achieving ≥75%        improvement (reduction) in Psoriasis Area and Severity Index        (PAST) score compared to baseline (also referred to as PASI 75)        are defined as treatment responders.    -   Partial response (partial responder): Patients achieving a ≥50%        improvement from baseline PASI score (also referred to as        PASI 50) but less than 75% (also referred to as PASI 75) are        defined as partial responders.    -   Non response (non-responder): Patients achieving a PASI        reduction of <50% from baseline PASI score are defined as        non-responders.    -   Relapse (relapser): If patients loose ≥50% of the PASI gain        achieved during the previous time in the study, patients will be        regarded as having a “relapse”.    -   Rebound (rebounder): Worsening of the value at baseline PASI (or        new pustular, erythrodermic or more inflammatory psoriasis        occurring within 8 weeks of stopping therapy), e.g., a PASI        of >125% of the value at baseline PASI.

In the PASI scoring system, the head, trunk, upper limbs and lower limbsare assessed separately for erythema, thickening (plaque elevation,induration), and scaling (desquamation) as defined in Table 1. Theaverage degree of severity of each sign in each of the four body regionsis assigned a score of 0 to 4. The area covered by lesions on each bodyregion is estimated as a percentage of the total area of that particularbody region. Because the head and neck, upper limbs, trunk and lowerlimbs correspond to approximately 10%, 20%, 30% and 40% of the bodysurface area, respectively, the PASI score is calculated using theformula:

PASI=0.1(EH+IH+DH)AH+0.2(EU+IU+DU)AU+0.3(ET+IT+DT)AT+0.4(EL+IL+DL)AL

PASI scores can range from a lower value of 0, corresponding to no signsof psoriasis, up to a theoretic maximum of 72.0. PASI scores arespecific to a tenth of a point, e.g., 9.0, 10.1, 14.2, 17.3, etc.Further information on PASI scoring is available in Henseler T,Schmitt-Rau K (2008) Int. J. Dermatol.; 47: 1019-1023.

TABLE 1 The PAST Scoring System Thickening (I) Scaling (D) Area score(A) (plaque levation, () (based on true Body Region Erythema (E)induration) desquamation area %)* Head and neck 0 = none 0 = none 0 =none 0 = 0% (H) 1 = slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2= moderate 2 = moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 =30-49% 4 = very severe 4 = very severe 4 = very severe 4 = 50-69% 5 =70-89% 6 = 90-100% Upper limbs (U) 0 = none 0 = none 0 = none 0 = 0% 1 =slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2 = moderate 2 =moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 = 30-49% 4 = verysevere 4 = very severe 4 = very severe 4 = 50-69% 5 = 70-89% 6 = 90-100%Trunk, axillae and 0 = none 0 = none 0 = none 0 = 0% groin (T) 1 =slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2 = moderate 2 =moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 = 30-49% 4 = verysevere 4 = very severe 4 = very severe 4 = 50-69% 5 = 70-89% 6 = 90-100%Lower limbs and 0 = none 0 = none 0 = none 0 = 0% buttocks (L) 1 =slight 1 = slight 1 = slight 1 = 1-9% 2 = moderate 2 = moderate 2 =moderate 2 = 10-29% 3 = severe 3 = severe 3 = severe 3 = 30-49% 4 = verysevere 4 = very severe 4 = very severe 4 = 50-69% 5 = 70-89% 6 = 90-100%

As used herein, the phrase “start of relapse” (SoR) refers to the lossof 15%-25%, of the maximum drug response (compared to baseline) achievedat any time before the visit at which the assessment of start of relapseis made and loss of PASI 75. In some embodiments of the disclosedmethods, uses and regimens, the psoriasis patient has experienced a SoR.In some embodiments of the disclosure, SoR refers to the loss of 20% ofthe maximum drug response (compared to baseline) achieved at any timebefore the visit at which the assessment of start of relapse is made andloss of PASI 75.

Table 2 provides several non-limiting examples of calculationsdetermining whether a patient displays “start of relapse” (“SoR”) usingthe PASI scoring system. The definition for SoR employed in Table 2 isloss of 20% of PASI gain and loss of PASI75 response. This definitionallows patients having a high response (either an initial response or aresponse following SoR treatment) to continue without additional dosingeven though they have lost 20% of the best improvement gain everachieved (see Patient 5 in Table 2). With a responder such as Patient 5,SoR treatment will not be initiated until PASI75 is lost (value F forPatient 5), nor will it be continued until PASI75 is again lost (value Kfor Patient 5).

TABLE 2 Examples of Start of Relapse, wherein Start or Relapse is lossof 20% of PASI gain and loss of PASI75 response. Item Patient 1 Patient2 Patient 3 Patient 4 Patient 5 Patient 6 (A) Baseline PASI Score 60.060.0 60.0 60.0 60.0 60.0 (B) PASI75 score = ¼A 15.0 15.0 15.0 15.0 15.015.0 Benchmark Example (C) Lowest PASI Score Ever 30.0 

15.0 15.0 5.0 2.5 10.0 Achieved (D) Best Improvement Gain Ever NA∞ 45.045.0 55.0 57.5 50.0 Achieved D = A − C (E) 20% Best Improvement Gain NA∞9.0 9.0 11.0 11.5 10.0 Ever Achieved E = 20% (D) (F) Start of relapsePASI score^(Ω) NA∞ 24.0 24.0 16.0 15.1* 20.0 F = C + E if C + E > B F =B + 0.1^(£) if C + E < B SoR Treatment Example{tilde over ( )} (G₁) NewPASI score NA∞ 18.0 18.0 4.0 2.0 14.0 following initial SoR treatment(G1). (G₂) New PASI score NA∞ 16.0 10.0 NA^(¥) NA^(¥) NA^(¥) followingcontinued administration (if required) (G) The lower of G₁ or G₂ or NA∞NA∞ 10.0 

4.0 

2.0 

14.0 G₁ if G₂ is NA. (H) New Improvement Gain NA∞ NA∞ 50.0 56.0 58.046.0 H = A − G (I) 20% New Improvement Gain NA∞ NA∞ 10.0 11.2 11.6 9.2 I= 20% (H) (J) Potential Next SoR PASI Score NA∞ NA∞ 20.0 15.2 13.6 20.0J = G + I if H > D J = F if H < D (K) Next SoR PASI Score 

 

NA∞ NA∞ 20.0 15.2 15.1 20.0 K = J if J > B K = B + 0.1 if J < B FurtherSoR Treatment . . .

 Not a candidate for SoR treatment because PASI75 not achieved (C > B).∞Not calculated because PASI75 not achieved (C > B). ^(Ω)When PASI scoreis greater than or equal to F, SoR Treatment is initiated. ^(£)The valueB + 0.1 is used to reflect a score greater than PASI75 (B), because PASIscores are specific to the nearest 0.1 decimal point. * In this example,because Patient 5 has responded very favorably to initial treatment,Patient 5 must loose PASI75 (i.e., have a PASI score of greater than 15(B), e.g., 15.1) to enter SoR treatment. {tilde over ( )}Once SoRtreatment has been initiated, a patient will be treated every 4 weeksuntil PASI75 (B) is achieved. Once PASI75 (B) is achieved, the patientwill again become eligible for SoR Treatment. ^(¥)No continuedadministration is needed, since PASI75 was already achieved in G₁.

 In these examples, the new PASI (G) is better than the Lowest PASIScore Ever Achieved (C), and therefore G will become the new benchmark,i e the new Lowest PASI Score Ever Achieved.

 

 When PAST score is greater than or equal to K, Further SoR Treatment isinitiated.

Table 2 illustrates, inter alia, that patients will not be eligible forSoR treatment until PASI75 is achieved (compare value B to value C forPatient 1). It also illustrates that some patients who initially receiveSoR treatment will not again be eligible for continued SoR treatment,because they do not achieve at least PASI75 (compare value B to value G₂for Patient 2).

In Table 2, it is also illustrated that a patient, once identified asexperiencing SoR, will be treated with the IL-17 binding molecule, e.g.,secukinumab, every 4 weeks until PASI75 (value B) is surpassed. In somecases, e.g., Patients 4-5, only a single dose of the IL-17 bindingmolecule, e.g., secukinumab, is required to again achieve PASI75 (valueG₁ for Patients 4-5). In other cases, e.g., Patient 3, more than onedose is required to again achieve PASI75 (value G₂ for Patient 3).

As shown in Table 2, once PASI75 is achieved during SoR treatment, a newcalculation is undertaken to determine the next SoR PASI score (valueK). In the case of Patients 3 and 4, because the new improvement gains(values H) following SoR treatment are the best improvement gain everachieved (compare H to D for each patient), those new improvement gains(values H) will be used in determining a new SoR PASI score (value K).However, in some situations, e.g., Patient 6, the new improvement gain(value H) following SoR treatment will not be the best improvement gainever achieved (compare H to D for Patient 6), and therefore the bestimprovement gain ever achieved (value D) will remain the benchmark indetermining the next SoR PASI score (value K).

It will be understood that maximum response, improvement, gainedimprovement, lost improvement, SoR, etc., may be measured by anyavailable scoring system, e.g., physician's assessed efficacy measures,such as PASI, visual assessment of index lesions, body surfacemeasurement (BSA), clinical signs score: Total Severity Sign score(TSS), Physician's global assessment of improvement (PGA) or otherglobal score (e.g., Investigators global assessment of improvement(IGA)); or patient's assessed efficacy measures, such as symptomimprovement (pruritis, soreness), Patient's assessment of globalimprovement, Patient's assessment of PASI (self-administeredPASI-SAPASI), or HRQL scales for dermatology (general scales, such asDLQI, DQOLS and specific psoriasis scales, such as PDI, PLSI)). In apreferred example, SoR is assessed using the PASI scoring system(physician assessed or patient assessed, preferably physician assessed).

If a patient has already displayed a SoR, and later displays anotherSoR, that subsequent relapse is referred to as an “additional start ofrelapse” or an “additional SoR”. In some embodiments of the disclosure,the patient has experienced an additional SoR.

As used herein, the phrases “has been previously treated with a systemicagent for psoriasis” and “prior psoriasis treatment” are used to mean apatient that has previously undergone psoriasis treatment using asystemic agent, e.g., the patient is a non-responder, a responder, arelapser, a rebounder, or a partial responder. Such patients includethose previously treated with biologics, such as efalizumab, and thosepreviously treated with non-biologics, such as cyclosporine. As usedherein, a patient having previously been treated for psoriasis withsecukinumab is referred to as having undergone “prior secukinumabtreatment”. In some embodiments of the disclosure, the patient has beenpreviously treated with a systemic agent for psoriasis.

As used herein, the phrase “has not been previously treated with asystemic agent for psoriasis” is used to mean a patient that has notpreviously undergone systemic psoriasis treatment. In some embodimentsof the disclosure, the patient has not been previously treated with asystemic agent for psoriasis.

As used herein, the term “naïve” refers to patient that has notpreviously undergone systemic psoriasis treatment. In some embodimentsof the disclosure, the patient is naïve.

By “therapeutic regimen” is meant the pattern of treatment of anillness, e.g., the pattern of dosing used during the treatment ofpsoriasis. A therapeutic regimen may include an induction regimen and amaintenance regimen. In some embodiments of the disclosure, the patientis given an induction regimen and a maintenance regimen of the IL-17antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g.,secukinumab, or IL-17 receptor binding molecule, e.g., IL-17 receptorantibody). Table 3 gives examples of approved therapeutic regimens fortreatment of psoriasis. Notably, none of these regimens provide fortreatment at SoR.

TABLE 3 Examples of therapeutic regimens for biological treatment ofpsoriasis Approved for any Induction Maintenance type of relapseStandard Route Regimen Regimen treatment adalimumab S.C. 80 mg once 40mg every No other week starting one week after initial dose alefaceptI.M. 15 mg once If the course is repeated No or weekly there must be agap of at I.V. for 12 least 12 weeks between weeks courses etanerceptS.C. 50 mg twice weekly 50 mg weekly No for 12 weeks infliximab I.V. 5mg/kg weeks 0, 2, 6 5 mg/kg every 8 weeks No ustekinumab S.C. Weight≤100 kg-45 mg 45 mg every 12 weeks No initially and 4 weeks later 90 mgevery 12 weeks Weight >100 kg-90 mg initially and 4 weeks later

The phrase “induction regimen” refers to a treatment regimen (or theportion of a treatment regimen) that is used for the initial treatmentof a disease. During the treatment of psoriasis, the first 12 weeks oftreatment is generally referred to as the “induction period”, and it isduring this time that an induction regimen is employed. The general goalof an induction regimen is to provide a high level of drug in the systemof a patient during the induction period. An induction regimen mayemploy (in part or in whole) a “loading regimen”, which may includeadministering a greater dose of the drug than a physician would employduring a maintenance regimen, administering a drug more frequently thana physician would administer the drug during a maintenance regimen, orboth. Delivery of an IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or an IL-17 receptorbinding molecule (e.g., an IL-17 receptor antibody) during an inductionregimen may be via a subcutaneous route, e.g., delivery of dosages ofabout 75 mg-about 300 mg s.c., via an intravenous route, e.g., deliveryof dosages of about 1 mg/kg,-about 50 mg/kg i.v. (e.g., about 1 mg/kg,about 3 mg/kg, about 10 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50mg/kg, etc.) or any other route of administration (e.g, intramuscular,i.m.). In some embodiments, the dose of the IL-17 binding molecule(e.g., secukinumab) used during an induction regimen is about 150 mg orabout 300 mg, which is delivered s.c.

An induction regimen for delivery of an IL-17 antagonist, e.g., an IL-17binding molecule (e.g., an IL-17 antibody, such as secukinumab) or anIL-17 receptor binding molecule (e.g., an IL-17 receptor antibody) mayalso be designed using PK information (see Table 11), rather thanspecific dosages. For the disclosed regimens and methods, an artisan maydeliver an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., anIL-17 antibody, such as secukinumab) or an IL-17 receptor bindingmolecule (e.g., an IL-17 receptor antibody) during an induction regimento provide a mean trough level of about 29.2 μg/mL (with a 30-40%inter-patient variation). Alternatively, an artisan may deliver an IL-17antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody,such as secukinumab) or an IL-17 receptor binding molecule (e.g., anIL-17 receptor antibody) during an induction regimen to provide aC_(max) for a typical 90 kg patient of between about 52 μg/ml-about 104μg/ml. In some embodiments, the IL-17 binding molecule (e.g., an IL-17antibody, e.g., secukinumab) has a T_(max) of about 7-8 days and anelimination half-life of about 30 days.

The phrase “maintenance regimen” refers to a treatment regimen (or theportion of a treatment regimen) that is used for the maintenance of apatient during treatment of an illness, e.g., to keep the patient inremission for longer periods of time (months or years). This time frameis referred to as a “maintenance period”. A maintenance regimen mayemploy continuous therapy (e.g., administering a drug at a regularintervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy(e.g., interrupted treatment, intermittent treatment, treatment atrelapse, or treatment upon achievement of a particular predeterminedcriteria [e.g., pain, disease manifestation, PASI score, etc.]).Delivery of an an IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or an IL-17 receptorbinding molecule (e.g., an IL-17 receptor antibody) during a maintenanceregimen may be via a subcutaneous route, e.g., delivery of dosages ofabout 75 mg-about 300 mg s.c., via an intravenous route, e.g., deliveryof dosages of about about 1 mg/kg-about 50 mg/kg i.v. (e.g., about 1mg/kg, about 3 mg/kg, about 10 mg/kg, about 30 mg/kg, about 40 mg/kg,about 50 mg/kg, etc.), or any other route of administration (e.g,intramuscular, i.m.). In some embodiments of the disclosed subjectmatter, the dose of the IL-17 binding molecule (e.g., secukinumab) usedduring a maintenance regimen is about 150 mg or about 300 mg (e.g.,delivered s.c.). A dose may be delivered as one or more than oneinjection, e.g., a dose of 150 mg may be delivered as two injections of75 mg and a dose of 300 mg may be delivered as two injections of 150 mg.

A maintenance regimen for delivery of an IL-17 antagonist, e.g., anIL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab) oran IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody)may also be designed using PK information (see Table 11), rather thanspecific dosages. For the disclosed regimens and methods, an artisan maydeliver an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., anIL-17 antibody, such as secukinumab) or an IL-17 receptor bindingmolecule (e.g., an IL-17 receptor antibody) during a maintenance regimento provide an average steady-state trough level of about 15 μg/mL (witha 30-40% inter-patient variation). Alternatively, an artisan may deliveran IL-17 binding molecule (e.g., an IL-17 antibody, e.g., secukinumab)during an induction regimen to provide an average steady-state troughlevel for a typical 90 kg patient of between about 5 μg/ml-about 70μg/ml, e.g., about 5 μg/ml-about 33 μg/ml or about 11 μg/ml-about 70μg/ml, preferably about 16 μg/ml or about 33 μg/ml. In some embodiments,the IL-17 binding molecule (e.g., an IL-17 antibody, e.g., secukinumab)has a T_(max) of about 7-8 days. In some embodiments, the IL-17 bindingmolecule (e.g., an IL-17 antibody, e.g., secukinumab) has an eliminationhalf-life of about 30 days.

In one embodiment, the maintenance regimen employs administration of atleast one (e.g., one or two doses) of the drug, e.g., a single dose ofsecukinumab, upon manifestation of predefined response criteria (e.g.,PASI scores or clinical signs indicating SoR). Such therapy is known asintermittent therapy (e.g., as compared to continuous therapy); a formof intermittent therapy is treatment at SoR. Administering secukinumabat SoR may be followed by monitoring the patient (or by the patientself-monitoring) for achievement of a predefined response criteria(e.g., PASI75). If the patient does not achieve the predefined responsecriteria following SoR treatment, then the patient may continuetreatment with the IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or an IL-17 receptorbinding molecule (e.g., an IL-17 receptor antibody) until thatpredefined response criteria is achieved. If the patient does achievethe predefined response criteria following SoR treatment, then treatmentwill be discontinued until an additional SoR occurs. If the patientmanifests a score indicative of an additional SoR, the patient may thenbe administered (or may self-administer) at least one (e.g., one or two)dose of secukinumab, e.g., another single dose of secukinumab. Thisprocess will repeat during SoR therapy. It will be recognized thattreatment at SoR provides a unique approach to psoriasis management, asit maintains the lowest level of drug exposure possible to achieve aclinically meaningful response, while allowing a patient to experience acompletely individualized therapy.

Accordingly, in some embodiments, a maintenance regimen may employadministration of the IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or an IL-17 receptorbinding molecule (e.g., an IL-17 receptor antibody) until a givenendpoint is met, e.g, achievement of PASI75. In further embodiments, themaintenance regimen comprises treating the patient with a dose of about75 mg-about 300 mg of the IL-17 binding molecule at start of relapse andthereafter treating the patient monthly with a dose of about 75 mg-about300 mg of the IL-17 binding molecule until PASI75 is achieved.

In some embodiments, once a patient experiences SoR (e.g., loss of 20%of the maximum response achieved at any time before the visit at whichthe assessment of SoR is made and loss of PASI 75), the patient will beadministered at least one (e.g., one, two, three, four, or more) dose ofthe IL-17 binding molecule (e.g., secukinumab), e.g., in monthly doses(every 4 weeks), which will continue until the predefined responsecriteria (e.g., PASI75) is again achieved. In another embodiment, once apatient experiences SoR (e.g., loss of 20% of the maximum responseachieved at any time before the visit at which the assessment of SoR ismade and loss of PASI 75), the patient is administered at least one dose(e.g., one, two, three, four, or more) of about 75 mg to about 300 mg(e.g., about 75 mg, about 150 mg, about 300 mg, preferably about 150 mgor about 300 mg) of the IL-17 binding molecule (e.g., IL-17 antibody,e.g, secukinumab) monthly until PASI75 is achieved. In some embodiments,the IL-17 binding molecule is administered to the patient shortly afterSoR is diagnosed (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, 21 days), and isthereafter administered on a monthly basis until PASI75 is achieved. Inother embodiments, a patient identified as displaying SoR will beadministered the IL-17 binding molecule at the next scheduledappointment and thereafter the patient will be administered the IL-17binding molecule on a monthly basis until PASI75 is achieved.

As used herein, “identifying a patient at start of relapse”, “identify apatient at start of relapse”, and the like, means that a patient, due tomanifestation of a certain predetermined score, e.g., a PASI score, isrecognized by a physician as displaying a SoR. In some embodiments, thedisclosed methods, regimens, and uses provide for identifying a patientat SoR.

The timing of dosing is generally measured from the day of the firstdose of secukinumab (which is also known as “baseline”). However, healthcare providers often use different naming conventions to identify dosingschedules, as shown in Table 4.

TABLE 4 Common naming conventions for dosing regimens. Week 0/1 1/2 2/33/4 4/5 5/6 6/7 7/8 8/9 9/10 10/11 etc 1^(st) day 0/1 7/8 14/15 21/2228/29 35/36 42/43 49/50 56/57 63/64 70/71 etc. of week Bolded itemsrefer to the naming convention used herein.

Notably, week zero may be referred to as week one by some health careproviders, while day zero may be referred to as day one by some healthcare providers. Thus, it is possible that different physicians willdesignate, e.g., a dose as being given during week 3/on day 21, duringweek 3/on day 22, during week 4/on day 21, during week 4/on day 22,while referring to the same dosing schedule. For consistency, the firstweek of dosing will be referred to herein as week 0, while the first dayof dosing will be referred to as day 1. However, it will be understoodby a skilled artisan that this naming convention is simply used forconsistency and should not be construed as limiting, i.e., weekly dosingis the provision of a weekly dose of the IL-17 binding moleculeregardless of whether the physician refers to a particular week as “week1” or “week 2”. As an example of naming using the convention designatedherein, five loading doses of secukinumab administered weekly during aninduction regimen may be provided during week 0 (e.g., on about day 1),during week 1 (e.g., on about day 8), during week 2 (e.g., on about day15), during week 3 (e.g., on about day 22), and during week 4 (e.g., onabout day 29). This portion of an induction regimen is also referred toas “weekly for five weeks”. Loading doses may be administered every twoweeks (i.e., every other week), e.g., during week 0, during week 2,during week 4, etc. Loading doses may be administered every three weeks,e.g., during week 0, during week 3, during week 6, etc. Loading dosesmay be administered daily for one week, e.g., on day 1-7.

During an induction regimen, an additional dose of secukinumab may beprovided at around day 57 (during week 8). This portion of an inductionregimen is referred to as “monthly” and this time point is referred toas being “during week eight”. Loading doses may also be administeredevery week (e.g., during week 0, 1, 2, 3, 4, etc.) or every other week,(e.g., during week 0, 2, 4, 6, 8, 10 etc.) Alternatively, a loading dosemay be delivered as a single high dose infusion (e.g., about 10 mg/kg,about 30 mg/kg) during the first month, and thereafter monthly s.c.injections may be administered (e.g., during week 4 and during week 8,etc.). Alternatively, a loading dose may be delivered as more than onehigh dose infusion (e.g., 3 doses of about 10 mg/kg) during the firstmonth, and thereafter monthly s.c. injections may be administered. Itwill be understood that a dose need not be provided at an exact timepoint, e.g., a dose due on day 57 could be provided, e.g., on day 52 today 62 (+/−5 days). In preferred embodiments, the induction regimenemploys dosing weekly for five weeks (week 0, 1, 2, 3, and 4), followedby a monthly dose during week 8.

For a maintenance regimen, a dose may be provided every month (alsocalled “monthly” dosing) (i.e., every 4 weeks, i.e., about every 28days), every two months (i.e., every 8 weeks, i.e., about every 56days), or every three months (i.e., every 12 weeks, i.e., about every 84days). As used herein, the first dose of a maintenance regimen employingcontinuous therapy will be administered on a date measured from thefinal dose of the induction regimen. Thus, as an example, if the finaldose of the induction regimen is provided during week 8, then the firstdose as part of a monthly maintenance regimen will be delivered duringweek 12, the first dose as part of an every two month maintenanceregimen will be delivered during week 16, the first dose as part of anevery three month maintenance regimen will be delivered during week 20,etc. In preferred embodiments, the maintenance regimen employs monthlydosing beginning on week 12.

As used herein, the phrase “means for administering” is used to indicateany available implement for systemically administering a biologic,including, but not limited to, a pre-filled syringe, a vial and syringe,an injection pen, an autoinjector, an i.v. drip and bag, a patch, a gel,a pump, etc. With such items, a patient may self-administer the drug(i.e., administer the drug on their own behalf) or a physician mayadminister the drug.

In some embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody, e.g, secukinumab) or IL-17 receptor bindingmolecule (e.g., IL-17 receptor antibody) may be administered as a doseof about 150 mg at weeks 0, 1, 2, 3, 4, and 8 followed by about 150 mgevery month (i.e., every 4 weeks) thereafter as a continuous maintenancetherapy. In some embodiments, the IL-17 antagonist, e.g., IL-17 bindingmolecule (e.g., IL-17 antibody, e.g, secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 receptor antibody) may be administered asa dose of about 300 mg at weeks 0, 1, 2, 3, 4, and 8 followed by about300 mg every month (i.e., every 4 weeks) thereafter as a continuousmaintenance therapy. In further embodiments, once a satisfactoryresponse is achieved, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody, e.g, secukinumab) or IL-17 receptor bindingmolecule (e.g., IL-17 receptor antibody) may be discontinued andsubsequent relapse managed with reintroduction of the IL-17 antagonist,e.g., IL-17 binding molecule (e.g., IL-17 antibody, e.g, secukinumab) orIL-17 receptor binding molecule (e.g., IL-17 receptor antibody) at theprevious effective dose as soon as a SoR or other loss of response isdetected.

In some embodiments, a booster dose may be employed during therapy withthe IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17antibody, e.g, secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 receptor antibody). A “booster dose”, as used herein, refers to adose (or several doses) of an IL-17 antagonist, e.g., IL-17 bindingmolecule (e.g., IL-17 antibody, e.g, secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 receptor antibody) that is greater thanthe standard doses delivered during psoriasis therapy with the IL-17binding molecule. For example, the dose of the IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody, e.g, secukinumab) or IL-17receptor binding molecule (e.g., IL-17 receptor antibody) may beescalated for patients who do not respond or who are partial respondersduring an induction period. Thus, a patient having been treated with 150mg of IL-17 binding molecule during week 0, 1, 2, 3, and 8 may beprovided with about 300 mg of the IL-17 binding molecule during week 12,and if the patient is then converted to a responder, the patient willthereafter be treated with doses of 150 mg. Alternatively, a physicianmay deliver a booster dose during week 16 (i.e., rather than during week12). In some embodiments, a physician may employ one or more boosterdoses (e.g., a single booster dose at week 12 and thereafter standarddoses, a booster dose at week 12 and 16 and thereafter standard doses,etc.). In some embodiments, if the original dose was 150 mg, the boosterwill be, e.g., about 300 mg or at least about 10 mg/kg (e.g., about 10mg/kg given 1, 2, 3, 4 or 5 times [e.g., twice a week, every week, everytwo weeks, every three weeks, etc.]; about 15 mg/kg given 1, 2, 3, 4 or5 times [e.g., twice a week, every week, every two weeks, every threeweeks, etc.]; about 20 mg/kg given 1, 2, 3, 4 or 5 times [e.g., twice aweek, every week, every two weeks, every three weeks, etc.]; about 30mg/kg given 1, 2, 3, 4 or 5 times [e.g., twice a week, every week, everytwo weeks, every three weeks, etc.], etc.). In some embodiments, if theoriginal dose was 300 mg, the booster will be, e.g., at least about 10mg/kg e.g., about 10 mg/kg given 1, 2, 3, 4 or 5 times [e.g., twice aweek, every week, every two weeks, every three weeks, etc.]; about 15mg/kg given 1, 2, 3, 4 or 5 times [e.g., twice a week, every week, everytwo weeks, every three weeks, etc.]; about 20 mg/kg given 1, 2, 3, 4 or5 times [e.g., twice a week, every week, every two weeks, every threeweeks, etc.]; about 30 mg/kg given 1, 2, 3, 4 or 5 times [e.g., twice aweek, every week, every two weeks, every three weeks, etc.], etc.). Insome embodiments, a partial responder or a non-responder is providedbooster doses for 4-8 weeks following the induction period.

In some embodiments, the maintenance regimen comprises treating thepatient with a booster dose of the IL-17 binding molecule that is higherthan the dose of the IL-17 binding molecule employed during theinduction regimen if the patient is a partial responder or anon-responder during the induction regimen.

In a preferred embodiment, the methods and uses of the IL-17 bindingmolecule provide treatment of moderate to severe chronic plaque-typepsoriasis in adult patients who are candidates for systemic therapy (orphototherapy). It is also expected that the methods and uses herein willprovide relief (i.e., reduction) from various signs and symptoms ofpsoriasis, including, e.g., psoriasis-related itching, flaking, peeling,cracking, pain, scaling and redness.

IL-17 Binding Molecules

The various disclosed pharmaceutical compositions, regimens uses,methods and kits utilize an IL-17 antagonist, e.g., IL-17 bindingmolecule (e.g., IL-17 antibody, e.g, secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 receptor antibody), such as secukinumab.

In one embodiment, the IL-17 binding molecule comprises at least oneimmunoglobulin heavy chain variable domain (V_(H)) comprising insequence hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having theamino acid sequence SEQ ID NO:1 (N-Y-W-M-N), said CDR2 having the aminoacid sequence SEQ ID NO:2 (A-I-N-Q-D-G-S-E-K-Y-Y-V-G-S-V-K-G), and saidCDR3 having the amino acid sequence SEQ ID NO:3(D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L).

In one embodiment, the IL-17 binding molecule comprises at least oneimmunoglobulin heavy chain variable domain (V_(H)) comprising insequence hypervariable regions CDR1-x, CDR2-x and CDR3-x, said CDR1-xhaving the amino acid sequence SEQ ID NO:11 (G-F-T-F—S-N-Y-W-M-N), saidCDR2-x having the amino acid sequence SEQ ID NO:12(A-I-N-Q-D-G-S-E-K-Y-Y), and said CDR3-x having the amino acid sequenceSEQ ID NO:13 (C-V-R-D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L-W-G).

In one embodiment, the IL-17 binding molecule comprises at least oneimmunoglobulin light chain variable domain (V_(L)) comprising insequence hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ havingthe amino acid sequence SEQ ID NO:4 (R-A-S-Q-S-V-S-S-S-Y-L-A), saidCDR2′ having the amino acid sequence SEQ ID NO:5 (G-A-S-S-R-A-T) andsaid CDR3′ having the amino acid sequence SEQ ID NO:6(Q-Q-Y-G-S-S-P-C-T).

In one embodiment, the IL-17 binding molecule comprises at least oneimmunoglobulin V_(H) domain and at least one immunoglobulin V_(L)domain, wherein: a) the immunoglobulin V_(H) domain comprises: i)hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the aminoacid sequence SEQ ID NO:1, said CDR2 having the amino acid sequence SEQID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; orii) hypervariable regions CDR1-x, CDR2-x and CDR3-x, said CDR1-x havingthe amino acid sequence SEQ ID NO:11, said CDR2-x having the amino acidsequence SEQ ID NO:12, and said CDR3-x having the amino acid sequenceSEQ ID NO:13; and b) the immunoglobulin V_(L) domain compriseshypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having theamino acid sequence SEQ ID NO:4, said CDR2′ having the amino acidsequence SEQ ID NO:5, and said CDR3′ having the amino acid sequence SEQID NO:6.

In one embodiment, the IL-17 binding molecule (e.g., IL-17 antibody,e.g., secukinumab) comprises at least one immunoglobulin V_(H) domainand at least one immunoglobulin V_(L) domain, wherein: a) the at leastone immunoglobulin V_(H) domain comprises in sequence hypervariableregions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequenceSEQ ID NO:1, said CDR2 having the amino acid sequence SEQ ID NO:2, andsaid CDR3 having the amino acid sequence SEQ ID NO:3; and b) the atleast one immunoglobulin V_(L) domain comprises in sequencehypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having theamino acid sequence SEQ ID NO:4, said CDR2′ having the amino acidsequence SEQ ID NO:5, and said CDR3′ having the amino acid sequence SEQID NO:6.

In one embodiment, the IL-17 binding molecule (e.g., IL-17 antibody,e.g., secukinumab) comprises at least one immunoglobulin V_(H) domainand at least one immunoglobulin V_(L) domain, wherein: a) the at leastone immunoglobulin V_(H) domain comprises in sequence hypervariableregions CDR1-x, CDR2-x and CDR3-x, said CDR1-x having the amino acidsequence SEQ ID NO:11, said CDR2-x having the amino acid sequence SEQ IDNO:12, and said CDR3-x having the amino acid sequence SEQ ID NO:13; andb) the at least one immunoglobulin V_(L) domain comprises in sequencehypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having theamino acid sequence SEQ ID NO:4, said CDR2′ having the amino acidsequence SEQ ID NO:5, and said CDR3′ having the amino acid sequence SEQID NO:6.

In one embodiment, the IL-17 binding molecule comprises:

-   -   a) an immunoglobulin heavy chain variable domain (V_(H))        comprising the amino acid sequence set forth as SEQ ID NO:8;    -   b) an immunoglobulin light chain variable domain (V_(L))        comprising the amino acid sequence set forth as SEQ ID NO:10;    -   c) an immunoglobulin V_(H) domain comprising the amino acid        sequence set forth as SEQ ID NO:8 and an immunoglobulin V_(L)        domain comprising the amino acid sequence set forth as SEQ ID        NO:10;    -   d) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3;    -   e) an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;    -   f) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID        NO:13;    -   g) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3        and an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;        or    -   h) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13        and an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

The amino acid sequences of the hypervariable regions of secukinumab,based on the Kabat definition and as determined by the X-ray analysisand using the approach of Chothia and coworkers, is provided in Table 5.

TABLE 5 Amino acid sequences of the hypervariableregions of the secukinumab monoclonal antibodies. Light-chain CDR1′Kabat definition R-A-S-Q-S-V-S-S-S-Y-L-A (SEQ ID NO: 4)Chothia/X-ray definition R-A-S-Q-S-V-S-S-S-Y-L-A (SEQ ID NO: 4) CDR2′Kabat definition G-A-S-S-R-A-T (SEQ ID NO: 5) Chothia/X-ray definitionG-A-S-S-R-A-T (SEQ ID NO: 5) CDR3′ Kabat definition Q-Q-Y-G-S-S-P-C-T(SEQ ID NO: 6) Chothia/X-ray definition Q-Q-Y-G-S-S-P-C-T (SEQ ID NO: 6)Heavy-chain CDR1 Kabat definition N-Y-W-M-N (SEQ ID NO: 1) CDR1-xChothia/X-ray definition G-F-T-F-S-N-Y-W-M-N (SEQ ID NO: 11) CDR2Kabat definition A-I-N-Q-D-G-S-E-K-Y-Y-V-G-S-V-K-G (SEQ ID NO: 2) CDR2-xChothia/X-ray definition A-I-N-Q-D-G-S-E-K-Y-Y (SEQ ID NO: 12) CDR3Kabat definition D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L (SEQ ID NO: 3)CDR3-x Chothia/X-ray definition C-V-R-D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L-W-G (SEQ ID NO: 13) Amino acid highlighted in bold are part of theCDR loops, while those shown in plain style are part of the antibodyframework.

In preferred embodiments, the variable domains of both heavy and lightchains are of human origin, for instance those of the secukinumabantibody which are shown in SEQ ID NO:10 (=variable domain of lightchain, i.e., amino acid 1 to 109 of SEQ ID NO:10) and SEQ ID NO:8(=variable domain of heavy chain, i.e., amino acid 1 to 127 of SEQ IDNO:8). The constant region domains preferably also comprise suitablehuman constant region domains, for instance as described in “Sequencesof Proteins of Immunological Interest”, Kabat E. A. et al, US Departmentof Health and Human Services, Public Health Service, National Instituteof Health.

In some embodiments, an IL-17 binding molecule of the disclosurecomprises the variable light domain of SEQ ID NO:10. In otherembodiments, an IL-17 binding molecule of the disclosure comprises thevariable heavy domain of SEQ ID NO:8. In other embodiments, an IL-17binding molecule of the disclosure comprises the variable light domainof SEQ ID NO:10 and the variable heavy domain of SEQ ID NO:8. In someembodiments, an IL-17 binding molecule of the disclosure comprises thethree CDRs of SEQ ID NO:10. In other embodiments, an IL-17 bindingmolecule of the disclosure comprises the three CDRs of SEQ ID NO:8. Inother embodiments, an IL-17 binding molecule of the disclosure comprisesthe three CDRs of SEQ ID NO:10 and the three CDRs of SEQ ID NO:8. CDRsof SEQ ID NO:8 and SEQ ID NO:10, according to both the Chothia and Kabatdefinition, may be found in Table 5.

In some embodiments, an IL-17 binding molecule of the disclosurecomprises the light domain of SEQ ID NO:15. In other embodiments, anIL-17 binding molecule of the disclosure comprises the heavy domain ofSEQ ID NO:17. In other embodiments, an IL-17 binding molecule of thedisclosure comprises the light domain of SEQ ID NO:15 and the heavydomain of SEQ ID NO:17. In some embodiments, an IL-17 binding moleculeof the disclosure comprises the three CDRs of SEQ ID NO:15. In otherembodiments, an IL-17 binding molecule of the disclosure comprises thethree CDRs of SEQ ID NO:17. In other embodiments, an IL-17 bindingmolecule of the disclosure comprises the three CDRs of SEQ ID NO:15 andthe three CDRs of SEQ ID NO:17. CDRs of SEQ ID NO:15 and SEQ ID NO:17,according to both the Chothia and Kabat definition, may be found inTable 5.

Hypervariable regions may be associated with any kind of frameworkregions, though preferably are of human origin. Suitable frameworkregions are described in Kabat E. A. et al, ibid. The preferred heavychain framework is a human heavy chain framework, for instance that ofthe secukinumab antibody. It consists in sequence, e.g. of FR1 (aminoacid 1 to 30 of SEQ ID NO:8), FR2 (amino acid 36 to 49 of SEQ ID NO:8),FR3 (amino acid 67 to 98 of SEQ ID NO:8) and FR4 (amino acid 117 to 127of SEQ ID NO:8) regions. Taking into consideration the determinedhypervariable regions of secukinumab by X-ray analysis, anotherpreferred heavy chain framework consists in sequence of FR1-x (aminoacid 1 to 25 of SEQ ID NO:8), FR2-x (amino acid 36 to 49 of SEQ IDNO:8), FR3-x (amino acid 61 to 95 of SEQ ID NO:8) and FR4 (amino acid119 to 127 of SEQ ID NO:8) regions. In a similar manner, the light chainframework consists, in sequence, of FR1′ (amino acid 1 to 23 of SEQ IDNO:10), FR2′ (amino acid 36 to 50 of SEQ ID NO:10), FR3′ (amino acid 58to 89 of SEQ ID NO:10) and FR4′ (amino acid 99 to 109 of SEQ ID NO:10)regions.

In one embodiment, an IL-17 binding molecule is selected from a humananti-IL-17 antibody that comprises at least: a) an immunoglobulin heavychain or fragment thereof which comprises a variable domain comprisingin sequence the hypervariable regions CDR1, CDR2 and CDR3 and theconstant part or fragment thereof of a human heavy chain; said CDR1having the amino acid sequence SEQ ID NO:1, said CDR2 having the aminoacid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequenceSEQ ID NO:3; and b) an immunoglobulin light chain or fragment thereofwhich comprises a variable domain comprising in sequence thehypervariable regions and optionally also the CDR1′, CDR2′, and CDR3′hypervariable regions and the constant part or fragment thereof of ahuman light chain, said CDR1′ having the amino acid sequence SEQ ID NO:4, said CDR2′ having the amino acid sequence SEQ ID NO:5, and said CDR3′having the amino acid sequence SEQ ID NO:6.

In one embodiment, an IL-17 binding molecule is selected from a singlechain binding molecule which comprises an antigen binding sitecomprising: a) a first domain comprising in sequence the hypervariableregions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequenceSEQ ID NO:1, said CDR2 having the amino acid sequence SEQ ID NO:2, andsaid CDR3 having the amino acid sequence SEQ ID NO: 3; and b) a seconddomain comprising the hypervariable regions CDR1′, CDR2′ and CDR3′, saidCDR1′ having the amino acid sequence SEQ ID NO:4, said CDR2′ having theamino acid sequence SEQ ID NO:5, and said CDR3′ having the amino acidsequence SEQ ID NO:6; and c) a peptide linker which is bound either tothe N-terminal extremity of the first domain and to the C-terminalextremity of the second domain or to the C-terminal extremity of thefirst domain and to the N-terminal extremity of the second domain.

Alternatively, an IL-17 binding molecule may comprise at least oneantigen binding site comprising at least one immunoglobulin heavy chainvariable domain (V_(H)) which comprises in sequence: a) hypervariableregions CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2) and CDR3 (SEQ ID NO:3); or b) hypervariable regions CDR1_(i), CDR2_(i), CDR3_(i), saidhypervariable region CDR1_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR1 asshown in SEQ ID NO: 1, said hypervariable region CDR2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR2 as shown in SEQ ID NO: 2; and said hypervariable regionCDR3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR3 as shown in SEQ ID NO: 3; and saidbinding IL-17 molecule is capable of inhibiting the activity of about 1nM (=30 ng/ml) human IL-17 at a concentration of about 50 nM or less,about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nMor less, or more preferably of about 1 nM or less of said molecule by50%, said inhibitory activity being measured on IL-6 production inducedby hu-IL-17 in human dermal fibroblasts.

Similarly, an IL-17 binding molecule may comprise at least one antigenbinding site comprising at least one immunoglobulin heavy chain variabledomain (V_(H)) which comprises in sequence: a) hypervariable regionsCDR1-x (SEQ ID NO: 11), CDR2-x (SEQ ID NO: 12) and CDR3-x (SEQ ID NO:13); orb) hypervariable regions CDR1_(i)-x, CDR2_(i)-x, CDR3_(i)-x, saidhypervariable region CDR1_(i)-x differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR1-x asshown in SEQ ID NO: 11, said hypervariable region CDR2_(i)-x differs by3, preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR2-x as shown in SEQ ID NO: 12; and said hypervariableregion CDR3_(i)-x differs by 3, preferably 2, more preferably 1 aminoacid(s) from the hypervariable region of CDR3-x as shown in SEQ ID NO:13; and said binding IL-17 molecule is capable of inhibiting theactivity of 1 nM (=30 ng/ml) human IL-17 at a concentration of about 50nM or less, about 20 nM or less, about 10 nM or less, about 5 nM orless, about 2 nM or less, or more preferably of about 1 nM or less ofsaid molecule by 50%, said inhibitory activity being measured on IL-6production induced by hu-IL-17 in human dermal fibroblasts.

Similarly, an IL-17 binding molecule may comprise at least one antigenbinding site comprising at least one immunoglobulin light chain variabledomain (V_(L)) which comprises in sequence: a) hypervariable regionsCDR′1 (SEQ ID NO: 4), CDR′2 (SEQ ID NO: 5) and CDR′3 (SEQ ID NO: 6); orb) hypervariable regions CDR1′_(i), CDR2′_(i), CDR3′_(i), saidhypervariable region CDR′1_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR′1 asshown in SEQ ID NO: 4, said hypervariable region CDR′2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR′2 as shown in SEQ ID NO: 5; and said hypervariable regionCDR′3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR′3 as shown in SEQ ID NO: 6; andsaid binding IL-17 molecule is capable of inhibiting the activity of 1nM (=30 ng/ml) human IL-17 at a concentration of about 50 nM or less,about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nMor less, or more preferably of about 1 nM or less of said molecule by50%, said inhibitory activity being measured on IL-6 production inducedby hu-IL-17 in human dermal fibroblasts.

Alternatively, an IL-17 binding molecule may comprise both heavy (V_(H))and light chain (V_(L)) variable domains and said IL-17 binding moleculehaving at least one antigen binding site comprising: a) animmunoglobulin heavy chain variable domain (V_(H)) which comprises insequence hypervariable regions CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2)and CDR3 (SEQ ID NO: 3); and an immunoglobulin light chain variabledomain (V_(L)) which comprises in sequence hypervariable regions CDR1′(SEQ ID NO: 4), CDR2′ (SEQ ID NO: 5) and CDR3′ (SEQ ID NO: 6); or b) animmunoglobulin heavy chain variable domain (V_(H)) which comprises insequence hypervariable regions CDR1_(i), CDR2_(i), and CDR3_(i), saidhypervariable region CDR1_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR1 asshown in SEQ ID NO: 1, said hypervariable region CDR2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR2 as shown in SEQ ID NO: 2; and said hypervariable regionCDR3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR3 as shown in SEQ ID NO: 3; and animmunoglobulin light chain variable domain (V_(L)) which comprises insequence hypervariable regions CDR1′_(i), CDR2′_(i), CDR3′_(i), saidhypervariable region CDR′ 1_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR′1 asshown in SEQ ID NO: 4, said hypervariable region CDR′2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR′2 as shown in SEQ ID NO: 5; and said hypervariable regionCDR′3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR′3 as shown in SEQ ID NO: 6; andsaid binding IL-17 molecule is capable of inhibiting the activity of 1nM (=30 ng/ml) human IL-17 at a concentration of about 50 nM or less,about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nMor less, or more preferably of about 1 nM or less of said molecule by50%, said inhibitory activity being measured on IL-6 production inducedby hu-IL-17 in human dermal fibroblasts.

Alternatively, an IL-17 binding molecule may comprise both heavy (V_(H))and light chain (V_(L)) variable domains and said IL-17 binding moleculecomprises at least one antigen binding site comprising: a) animmunoglobulin heavy chain variable domain (V_(H)) which comprises insequence hypervariable regions CDR1-x (SEQ ID NO:11), CDR2-x (SEQ IDNO:12) and CDR3-x (SEQ ID NO:13); and an immunoglobulin light chainvariable domain (V_(L)) which comprises in sequence hypervariableregions CDR1′ (SEQ ID NO: 4), CDR2′ (SEQ ID NO: 5) and CDR3′ (SEQ IDNO:6); orb) an immunoglobulin heavy chain variable domain (V_(H)) whichcomprises in sequence hypervariable regions CDR1_(i)-x, CDR2_(i)-x, andCDR3_(i)-x, said hypervariable region hypervariable regions CDR1_(i)-x,CDR2_(i)-x, CDR3_(i)-x, said hypervariable region CDR1_(i)-x differs by3, preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR1-x as shown in SEQ ID NO: 11, said hypervariable regionCDR2_(i)-x differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR2-x as shown in SEQ ID NO: 12; andsaid hypervariable region CDR3_(i)-x differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR3-x asshown in SEQ ID NO: 13; and an immunoglobulin light chain variabledomain (V_(L)) which comprises in sequence hypervariable regionsCDR1′_(i), CDR2′_(i), CDR3′_(i), said hypervariable region CDR′1_(i)differs by 3, preferably 2, more preferably 1 amino acid(s) from thehypervariable region of CDR′1 as shown in SEQ ID NO: 4, saidhypervariable region CDR′2_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR′2 asshown in SEQ ID NO:5; and said hypervariable region CDR′3_(i) differs by3, preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR′3 as shown in SEQ ID NO: 6; and said binding IL-17molecule is capable of inhibiting the activity of 1 nM (=30 ng/ml) humanIL-17 at a concentration of about 50 nM or less, about 20 nM or less,about 10 nM or less, about 5 nM or less, about 2 nM or less, or morepreferably of about 1 nM or less of said molecule by 50%, saidinhibitory activity being measured on IL-6 production induced byhu-IL-17 in human dermal fibroblasts.

A human IL-17 antibody disclosed herein may comprise a heavy chain thatis substantially identical to that set forth as SEQ ID NO:17 and a lightchain that is substantially identical to that set forth as SEQ ID NO:15.A human IL-17 antibody disclosed herein may comprise a heavy chain thatcomprises SEQ ID NO:17 and a light chain that comprises SEQ ID NO:15.

A human IL-17 antibody disclosed herein may comprise: a) one heavy chainwhich comprises a variable domain having an amino acid sequencesubstantially identical to that shown in SEQ ID NO:8 and the constantpart of a human heavy chain; and b) one light chain which comprises avariable domain having an amino acid sequence substantially identical tothat shown in SEQ ID NO:10 and the constant part of a human light chain.

The inhibition of the binding of IL-17 to its receptor may beconveniently tested in various assays including such assays as describedin WO 2006/013107. By the term “to the same extent” is meant that thereference and the equivalent molecules exhibit, on a statistical basis,essentially identical IL-17 inhibitory activity in one of the assaysreferred to herein (see Example 1 of WO 2006/013107). For example, IL-17binding molecules of the disclosure typically have IC₅₀s for theinhibition of human IL-17 on IL-6 production induced by human IL-17 inhuman dermal fibroblasts which are below about 10 nM, more preferablyabout 9, 8, 7, 6, 5, 4, 3, 2, or about 1 nM of that of, preferablysubstantially the same as, the IC₅₀ of the corresponding referencemolecule when assayed as described in Example 1 of WO 2006/013107.Alternatively, the assay used may be an assay of competitive inhibitionof binding of IL-17 by soluble IL-17 receptors (e.g. the human IL-17R/Fc constructs of Example 1 of WO 2006/013107) and the IL-17 bindingmolecules of the disclosure.

The disclosure also includes IL-17 binding molecules in which one ormore of the amino acid residues of CDR1, CDR2, CDR3, CDR1-x, CDR2-x,CDR3-x, CDR1′, CDR2′ or CDR3′ or the frameworks, typically only a few(e.g., 1-4), are changed; for instance by mutation, e.g., site directedmutagenesis of the corresponding DNA sequences. The disclosure includesthe DNA sequences coding for such changed IL-17 binding molecules. Inparticular the disclosure includes IL-17 binding molecules in which oneor more residues of CDR1′ or CDR2′ have been changed from the residuesshown in SEQ ID NO:4 (for CDR1′) and SEQ ID NO:5 (for CDR2′).

The disclosure also includes IL-17 binding molecules that have bindingspecificity for human IL-17, in particular IL-17 antibodies capable ofinhibiting the binding of IL-17 to its receptor and IL-17 antibodiescapable of inhibiting the activity of 1 nM (=30 ng/ml) human IL-17 at aconcentration of about 50 nM or less, about 20 nM or less, about 10 nMor less, about 5 nM or less, about 2 nM or less, or more preferably ofabout 1 nM or less of said molecule by 50% (said inhibitory activitybeing measured on IL-6 production induced by hu-IL-17 in human dermalfibroblasts).

In some embodiments, the IL-17 binding molecule, e.g., IL-17 antibody,e.g., secukinumab, binds to an epitope of mature human IL-17 comprisingLeu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127,Val128, His129. In some embodiments, the IL-17 antibody, e.g.,secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43,Tyr44, Arg46, Ala79, Asp80. In some embodiments, the IL-17 antibody,e.g., secukinumab, binds to an epitope of an IL-17 homodimer having twomature human IL-17 chains, said epitope comprising Leu74, Tyr85, His86,Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on onechain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain. Theresidue numbering scheme used to define these epitopes is based onresidue one being the first amino acid of the mature protein (ie.,IL-17A lacking the 23 amino acid N-terminal signal peptide and beginningwith Glycine). The sequence for immature IL-17A is set forth in theSwiss-Prot entry Q16552. In some embodiments, the IL-17 antibody has aK_(D) of about 100-200 pM. In some embodiments, the IL-17 antibody hasan IC₅₀ of about 0.4 nM for in vitro neutralization of the biologicalactivity of about 0.67 nM human IL-17A. In some embodiments, the IL-17antibody has an in vivo half-life of about 4 weeks (e.g., about 23 toabout 30 days). In some embodiments, the absolute bioavailability ofsubcutaneously (s.c.) administered IL-17 antibody has a range of about60-about 80%, e.g., about 76%.

Particularly preferred IL-17 binding molecules of the disclosure arehuman antibodies, especially secukinumab, as described in Examples 1 and2 of WO 2006/013107. Secukinumab (AIN457) is a recombinanthigh-affinity, fully human monoclonal anti-human interleukin-17A(IL-17A, IL-17) antibody of the IgG1/kappa isotype that is currently inclinical trials for the treatment of immune-mediated inflammatoryconditions.

Treatment Regimens, Methods of Treatment, Pharmaceutical Compositionsand Uses

The disclosed IL-17 antagonists, e.g., IL-17 binding molecules, e.g., anIL-17 antibody, such as secukinumab, are useful for the treatment,prevention, or amelioration of psoriasis.

The IL-17 antagonists, e.g., IL-17 binding molecules, e.g., an IL-17antibody, such as secukinumab, may be used in vitro, ex vivo, orincorporated into pharmaceutical compositions and administered toindividuals (e.g., human subjects) in vivo to treat, ameliorate, orprevent psoriasis. A pharmaceutical composition will be formulated to becompatible with its intended route of administration (e.g., oralcompositions generally include an inert diluent or an edible carrier).Other nonlimiting examples of routes of administration includeparenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g.,inhalation), transdermal (topical), transmucosal, and rectaladministration. The pharmaceutical compositions compatible with eachintended route are well known in the art.

The IL-17 antagonists, e.g., IL-17 binding molecules, e.g., an IL-17antibody, such as secukinumab, may be used as a pharmaceuticalcomposition when combined with a pharmaceutically acceptable carrier.Such a composition may contain, in addition to an IL-17 bindingmolecule, carriers, various diluents, fillers, salts, buffers,stabilizers, solubilizers, and other materials well known in the art.The characteristics of the carrier will depend on the route ofadministration.

The pharmaceutical compositions for use in the disclosed methods mayalso contain additional therapeutic agents for treatment of theparticular targeted disorder. For example, a pharmaceutical compositionmay also include anti-inflammatory agents. Such additional factorsand/or agents may be included in the pharmaceutical composition toproduce a synergistic effect with the IL-17 binding molecules, or tominimize side effects caused by the IL-17 binding molecules.

The pharmaceutical composition of the disclosure may be in the form of aliposome in which the IL-17 binding molecule is combined, in addition toother pharmaceutically acceptable carriers, with amphipathic agents suchas lipids that exist in aggregated form as micelles, insolublemonolayers, liquid crystals, or lamellar layers in aqueous solution.Suitable lipids for liposomal formulation include, without limitation,monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids,saponin, bile acids, etc.

In practicing the method of treatment or use of the present disclosure,a therapeutically effective amount of an IL-17 binding molecule isadministered to a subject, e.g., a mammal (e.g., a human). An IL-17binding molecule may be administered in accordance with the method ofthe disclosure either alone or in combination with other therapies, suchas, e.g., in combination with additional therapies for inflammation.When coadministered with one or more agents, an IL-17 binding moleculemay be administered either simultaneously with the other agent, orsequentially. If administered sequentially, the attending physician willdecide on the appropriate sequence of administering the IL-17 bindingmolecule in combination with other agents.

When a therapeutically effective amount of an IL-17 binding molecule isadministered orally, the binding agent will be in the form of a tablet,capsule, powder, solution or elixir. When administered in tablet form,the pharmaceutical composition of the disclosure may additionallycontain a solid carrier such as a gelatin or an adjuvant. Whenadministered in liquid form, a liquid carrier such as water, petroleum,oils of animal or plant origin such as peanut oil (exercising caution inrelation to peanut allergies), mineral oil, soybean oil, or sesame oil,or synthetic oils may be added. The liquid form of the pharmaceuticalcomposition may further contain physiological saline solution, dextroseor other saccharide solution, or glycols such as ethylene glycol,propylene glycol, or polyethylene glycol.

When a therapeutically effective amount of an IL-17 binding molecule isadministered by intravenous, cutaneous or subcutaneous injection, theIL-17 binding molecule will be in the form of a pyrogen-free,parenterally acceptable solution. A pharmaceutical composition forintravenous, cutaneous, or subcutaneous injection may contain, inaddition to the IL-17 binding molecule, an isotonic vehicle such assodium chloride injection, Ringer's injection, dextrose injection,dextrose and sodium chloride injection, lactated Ringer's injection, orother vehicle as known in the art.

Pharmaceutical compositions for use in the disclosed methods may bemanufactured in conventional manner. In one embodiment, thepharmaceutical composition is preferably provided in lyophilized form.For immediate administration it is dissolved in a suitable aqueouscarrier, for example sterile water for injection or sterile bufferedphysiological saline. If it is considered desirable to make up asolution of larger volume for administration by infusion rather than abolus injection, it is advantageous to incorporate human serum albuminor the patient's own heparinised blood into the saline at the time offormulation. The presence of an excess of such physiologically inertprotein prevents loss of antibody by adsorption onto the walls of thecontainer and tubing used with the infusion solution. If albumin isused, a suitable concentration is from 0.5 to 4.5% by weight of thesaline solution. Other formulations comprise liquid or lyophilizedformulation.

The appropriate dosage will, of course, vary depending upon, forexample, the particular IL-17 binding molecule to be employed, the host,the mode of administration and the nature and severity of the conditionbeing treated, and on the nature of prior treatments that the patienthas undergone. Ultimately, the attending physician will decide theamount of the IL-17 binding molecule with which to treat each individualsubject. In some embodiments, the attending physician may administer lowdoses of the IL-17 binding molecule and observe the subject's response.In other embodiments, the initial dose(s) of IL-17 binding moleculeadministered to a subject are high, and then are titrated downward untilsigns of relapse occur. Larger doses of the IL-17 binding molecule maybe administered until the optimal therapeutic effect is obtained for thesubject, and at that point the dosage is not generally increasedfurther.

An IL-17 binding molecule is conveniently administered parenterally,intravenously, e.g. into the antecubital or other peripheral vein,intramuscularly, or subcutaneously. The duration of intravenous (i.v.)therapy using a pharmaceutical composition of the present disclosurewill vary, depending on the severity of the disease being treated andthe condition and personal response of each individual patient. Alsocontemplated is subcutaneous (s.c.) therapy using a pharmaceuticalcomposition of the present disclosure. The attending physician willdecide on the appropriate duration of i.v. or s.c. therapy and thetiming of administration of the therapy, using the pharmaceuticalcomposition of the present disclosure.

Satisfactory results (treatment, prophylaxis, delay of onset ofsymptoms) are generally indicated to be obtained at dosages from about0.05 mg to about 20 mg per kilogram body weight, more usually from about0.1 mg to about 20 mg per kilogram body weight. The frequency of dosingmay be in the range from about once per week up to about once everythree months, e.g., in the range from about once every 2 weeks up toabout once every 12 weeks, e.g., once every four to eight weeks. Thedosing frequency will depend on, inter alia, the phase of the treatmentregimen.

In some embodiments, an IL-17 binding molecule (e.g., IL-17 antibody,such as secukinumab) is administered during an induction regimen and/ormaintenance regimen. In some embodiments, the induction regimencomprises a loading regimen. In further embodiments, the loading regimencomprises administration of 1, 2, 3, 4, 5, 6, or more weekly doses ofsecukinumab, preferably five weekly doses of secukinumab (e.g.,delivered during weeks 0, 1, 2, 3,4). In some embodiments, the loadingregimen comprises administration of daily doses of secukinumab, e.g.,daily doses of secukinumab delivered for one week. In some embodiments,the loading dosage that may be administered in these weekly or dailyamounts may be about 25 mg-about 300 mg delivered s.c., e.g., about 150mg-about 300 mg s.c, e.g., about 150 mg or about 300 mg delivered s.c.In other embodiments, the induction regimen, in addition to including aloading regimen, further comprises delivery of secukinumab as monthlydoses, e.g., 1, 2, 3, 4, 5 or more monthly doses of secukinumab,preferably one monthly dose of secukinumab delivered at week eight.

In some embodiments, the maintenance regimen comprises administration ofan IL-17 binding molecule (e.g., IL-17 antibody, such as secukinumab)(e.g., about 75 mg-about 300 mg delivered s.c., e.g., about 150 mg-about300 mg s.c, e.g., about 150 mg or about 300 mg) in a continuous fashiondelivered bimonthly, monthly, every two months or every three months. Ina preferred embodiment, a maintenance dose is delivered monthly. In someembodiments, if the dose during the maintenance regimen is deliveredmonthly, the first monthly dose is delivered on week 12, and thenmonthly (e.g., about every 4 weeks or about every 28 days) thereafter.In some embodiments, if the dose during the maintenance regimen isdelivered every two months, the first dose is delivered on week 16, andthen every two months (e.g., about every 8 weeks or about every 56 days)thereafter. In some embodiments, if the dose during the maintenanceregimen is delivered every three months, the first dose is delivered onweek 20, and then every three months (e.g., about every 12 weeks orabout every 84 days) thereafter.

In some embodiments, the maintenance regimen comprises intermittentadministration of an IL-17 binding molecule (e.g., IL-17 antibody, suchas secukinumab) (e.g., about 75 mg-about 300 mg delivered s.c., e.g.,about 150 mg-about 300 mg s.c, e.g., about 150 mg or about 300 mg) asone or two doses (e.g., a single dose) following SoR. Following theseone or two doses, the patient is monitored for an additional SoR asdefined herein. Upon observation of an additional SoR (which can bedetermined using any acceptable dermatological scoring system,preferably the PASI scoring system), the patient may be administered anadditional one or two doses (e.g., a single dose) of secukinumab. Thistreatment at SoR may be continued for the life of the patient, as longas the patient's psoriatic symptoms are efficiently retreated withintermittent therapy delivered at SoR (e.g., the relapse PASI score canbe improved to an acceptable PASI score). In some embodiments, SoR isdefined as the loss of 20% of the maximum PASI response achieved at anytime before the visit at which the assessment of start of relapse ismade and loss of PASI 75.

In some embodiments, the maintenance regimen following SoR comprisesadministration of at least one dose (e.g., one, two, three, four, ormore) of secukinumab (e.g., about 75 mg-about 300 mg delivered s.c.,e.g., about 150 mg-about 300 mg s.c, e.g., about 150 mg or about 300 mg)until a given endpoint is met, e.g., achievement of PASI75. In apreferred embodiment, once a patient experiences SoR, the patient iss.c. administered at least one dose (e.g., one, two, three, four, ormore) of about 75 mg-about 300 mg (e.g., about 75 mg, about 150 mg,about 300 mg, preferably about 150 mg or about 300 mg) of the IL-17binding molecule (e.g., secukinumab) monthly until PASI75 is achieved.

Should intermittent therapy, e.g., treatment at SoR, no longer improve apatient's psoriatic symptoms (e.g., the relapse PASI score can no longerbe improved to an acceptable PASI score, e.g., PASI75), then the patientmay enter into continuous therapy. In a maintenance regimen employingcontinuous therapy, the patient may be administered secukinumab (e.g.,about 150 mg-about 300 mg s.c., e.g., about 150 mg or about 300 mg s.c.)weekly, bimonthly, monthly, every two months or every three months.Alternatively, a maintenance regimen may begin as an intermittenttherapy (e.g., treatment SoR), but may be switched to a continuoustherapy. For example, if a patient shows regular intervals between SoR,a physician might decide to switch the patient to continuous treatment,but using a particular interval identified for that individual patient(rather than a pre-defined interval). This would result in a“semi-individualized” approach, rather than a completely individualizedapproach during which each dose is triggered by SoR. For example, if apatient persistently presents with SoR scores every 5-6 weeks, then aphysician may switch the patient from intermittent therapy (treatment atSoR) to continuous administration of secukinumab every five or sixweeks.

In some embodiments, the dosage of secukinumab used in the disclosedinduction and/or maintenance regimens is based on the patient's weight.In one embodiment, the patient is administered about 150 mg s.c. if thepatient weighs less than or equal to about 90 kg. In one embodiment, thepatient is administered about 150 mg s.c. if the patient weighs lessthan or equal to about 100 kg. In another embodiment, the patient isadministered about 300 mg s.c. if the patient weighs more than about 90kg. In another embodiment, the patient is administered about 300 mg s.c.if the patient weighs more than about 100 kg. Other types ofweight-based dosing for use in the disclosed methods include, e.g., 75mg for less than 70 kg, 150 mg for less than 90 kg, 300 mg for greaterthan or equal to 90 kg. Furthermore, an artisan could also administerthe IL-17 binding molecule based on a combination of bodyweight-baseddosing and response-based dosing, e.g., non-responders to 150 mg whoare, e.g., less than 70 kg, are escalated to 300 mg.

It will be understood that dose escalation may be required (e.g., duringthe induction and/or maintenance phase) for certain patients, e.g.,patients that display partial response non-response to treatment withthe IL-17 binding molecules (e.g., secukinumab). Thus, dosages ofsecukinumab may be greater than about 75 mg to about 300 mg s.c., e.g.,about 80 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg,about 250 mg, about 350 mg, about 400 mg, etc. It will also beunderstood that dose reduction may also be required (e.g., during theinduction and/or maintenance phase) for certain patients, e.g., patientsthat display adverse events or an adverse response to treatment with theIL-17 binding molecules (e.g., secukinumab). Thus, dosages ofsecukinumab may be less than about 75 mg to about 300 mg s.c., e.g.,about 25 mg, about 50 mg, about 80 mg, about 100 mg, about 125 mg, about175 mg, about 200 mg, 250 mg, etc.

Disclosed herein are methods of treating psoriasis, comprising: a)administering an IL-17 binding molecule to a patient in need thereofduring an induction regimen, wherein the induction regimen comprises aloading regimen, wherein the loading regimen comprises administering thepatient five doses of about 75 mg-about 300 mg (e.g., about 150 mg-about300 mg) of the IL-17 binding molecule, each of the five doses beingdelivered weekly, beginning on week zero; and b) thereafteradministering the IL-17 binding molecule to the patient during amaintenance regimen.

In some embodiments, the five doses of the IL-17 binding molecule areabout 75 mg-about 300 mg each. In some embodiments, the five doses areeach about 150 mg or about 300 mg each. In some embodiments, the fivedoses of about 150 mg are administered to the patient if the patientweighs less than 90 kg and wherein the five doses of about 300 mg areadministered to the patient if the patient weighs more than or equal to90 kg. In some embodiments, the induction regimen further comprisesadministering the patient about 75 mg-about 300 mg of the IL-17 bindingmolecule during week eight.

In some embodiments, the maintenance regimen comprises treating thepatient with about 75 mg-about 300 mg of the IL-17 binding moleculemonthly, every two months or every three months. In some embodiments,the maintenance regimen comprises treating the patient with at least onedose of about 75 mg-about 300 mg of the IL-17 binding molecule at startof relapse. In some embodiments, the maintenance regimen furthercomprises treating the patient with at least one dose of about 75mg-about 300 mg of the IL-17 binding molecule at each additional startof relapse. In some embodiments, the maintenance regimen comprisestreating the patient with a dose of about 75 mg-about 300 mg of theIL-17 binding molecule at start of relapse and thereafter treating thepatient monthly with a dose of about 75 mg-about 300 mg of the IL-17binding molecule until PASI75 is achieved. In some embodiments, themaintenance regimen comprises treating the patient with a booster doseof the IL-17 binding molecule that is higher than the dose of the IL-17binding molecule employed during the induction regimen if the patient isa partial responder or a non-responder to treatment with the IL-17binding molecule during the induction regimen.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that at least one dose of the IL-17 bindingmolecule is administered to a patient at start of relapse from a priortreatment with the IL-17 binding molecule. Also disclosed herein aremethods of treating psoriasis, comprising: a) identifying a patient atstart of relapse from a prior psoriasis treatment employing an IL-17binding molecule; and b) administering to the patient at least one doseof the IL-17 binding molecule.

In some embodiments, the at least one dose of the IL-17 binding moleculeis about 75 mg-about 300 mg each. In some embodiments, the at least onedose of the IL-17 binding molecule is about 150 mg or about 300 mg each.In some embodiments, steps a) and b) are repeated.

In some embodiments, the prior treatment with the IL-17 binding moleculecomprises an induction regimen. In some embodiments, the inductionregimen comprises a loading regimen. In some embodiments, the loadingregimen comprises administering the patient five doses of about 75mg-about 300 mg of the IL-17 binding molecule, each of the five dosesbeing delivered weekly, beginning on week zero. In some embodiments, thefive doses are each about 150 mg or about 300 mg. In some embodiments,the five doses of about 150 mg are administered to the patient if thepatient weighs less than 90 kg and wherein the five doses of about 300mg are administered to the patient if the patient weighs more than orequal to 90 kg. In some embodiments, the induction regimen furthercomprises administering the patient about 75 mg-about 300 mg the IL-17binding molecule during week eight.

In some embodiments, the prior treatment with the IL-17 binding moleculecomprises administering to the patient at least one dose of the IL-17binding molecule at start of relapse.

Disclosed herein are methods of treating psoriasis, comprising: a)administering a patient in need thereof five doses of about 75 mg-about300 mg (e.g., about 150 mg-about 300 mg) of an IL-17 binding molecule,each of the five doses being delivered weekly, beginning on week zero;b) administering the patient about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) the IL-17 binding molecule during week eight; c)administering the patient at least one dose of about 75 mg-about 300 mg(e.g., about 150 mg-about 300 mg) the IL-17 binding molecule at start ofrelapse; and d) repeating step c) at each additional start of relapse.

Disclosed herein are therapeutic regimens for treating psoriasis,comprising:

a) administering an IL-17 binding molecule to a patient in need thereofduring an induction regimen comprising; i. administering about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) of the IL-17 bindingmolecule to the patient weekly for five weeks, wherein the first dose ofthe IL-17 binding molecule is administered during week zero; and ii.thereafter administering about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) of the IL-17 binding molecule to the patient duringweek eight; andb) administering the IL-17 binding molecule to the patient during amaintenance regimen comprising; i. administering about 75 mg-about 300mg (e.g., about 150 mg-about 300 mg) of the IL-17 binding molecule tothe patient each month, every two months or every three months; or ii.administering at least one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg) of the IL-17 binding molecule to the patient atstart of relapse.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered during an induction regimen, wherein the induction regimencomprises a loading regimen, wherein the loading regimen comprisesadministering five doses of about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) of the IL-17 binding molecule, each of the five dosesbeing delivered weekly, beginning on week zero; and b) thereafter, is tobe administered during a maintenance regimen.

In some embodiments, the loading regimen comprises administering fivedoses of about 150 mg or about 300 mg of the IL-17 binding molecule. Insome embodiments, the five doses of about 150 mg are administered to thepatient if the patient weighs less than 90 kg and wherein the five dosesof about 300 mg are administered to the patient if the patient weighsmore than or equal to 90 kg. In some embodiments, the induction regimenfurther comprises administering the patient about 75 mg-about 300 mg ofthe IL-17 binding molecule during week eight.

In some embodiments, the maintenance regimen comprises treating thepatient with about 75 mg-about 300 mg of the IL-17 binding moleculemonthly, every two months or every three months. In some embodiments,the maintenance regimen comprises treating the patient with at least onedose of about 75 mg-about 300 mg of the IL-17 binding molecule at startof relapse. In some embodiments, the maintenance regimen furthercomprises treating the patient with at least one dose of about 75mg-about 300 mg of a the IL-17 binding molecule at each additional startof relapse.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule is: a) to beadministered to a patient in need thereof as five doses of about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg), each of the fivedoses being delivered weekly, beginning on week zero; b) thereafter tobe administered to the patient during week eight in an amount of about75 mg-about 300 mg (e.g., about 150 mg-about 300 mg); c) thereafter tobe administered to the patient as at least one dose of about 75 mg-about300 mg (e.g., about 150 mg-about 300 mg) at start of relapse; and d)thereafter to be administered to the patient at start of each additionalrelapse as at least one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg).

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule is:

a) to be administered to a patient in need thereof during an inductionregimen comprising; i. the IL-17 binding molecule is to be administeredto the patient at a dose of about 75 mg-about 300 mg (e.g., about 150mg-about 300 mg) weekly for five weeks, wherein the first dose of theIL-17 binding molecule is to be administered during week zero; and ii.thereafter the IL-17 binding molecule is to be administered to thepatient at a dose of about 75 mg-about 300 mg (e.g., about 150 mg-about300 mg) during week eight; and

b) to be administered to the patient during a maintenance regimencomprising; i. the IL-17 binding molecule is to be administered to thepatient at a dose of about 75 mg-about 300 mg (e.g., about 150 mg-about300 mg) each month, every two months or every three months; or ii. theIL-17 binding molecule is to be administered to the patient as at leastone dose of about 75 mg-about 300 mg (e.g., about 150 mg-about 300 mg)of the IL-17 binding molecule at start of relapse.

Disclosed herein are uses of IL-17 binding molecules for the manufactureof a medicament for treating psoriasis, characterized in that the IL-17binding molecule is to be administered to a patient at start of relapsefrom a prior treatment with the IL-17 binding molecule.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis in a patient, wherein said patient is to be identified atstart of relapse from a prior treatment with the IL-17 binding moleculeand wherein said patient is to be administered at least one dose of theIL-17 binding molecule.

Disclosed herein are pharmaceutical compositions for treating psoriasis,comprising as an active ingredient and the IL-17 binding molecule,wherein the IL-17 binding molecule is to be administered to a patient atstart of relapse from a prior treatment with the IL-17 binding molecule.

Disclosed herein are methods of treating psoriasis, comprising: a)administering a patient in need thereof five weekly doses of about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) of an IL-17 bindingmolecule; and b) thereafter administering: i) about 75 mg-about 300 mg(e.g., about 150 mg-about 300 mg) of the IL-17 binding molecule to thepatient monthly or ii) one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg) of the IL-17 binding molecule to the patient aboutone month following step a) and thereafter administering at least onedose of about 75 mg-about 300 mg (e.g., about 150 mg-about 300 mg) ofthe IL-17 binding molecule to the patient at start of relapse.

Disclosed herein are therapeutic regimens for treating psoriasis,comprising: a) administering a patient in need thereof five weekly dosesof about 75 mg-about 300 mg (e.g., about 150 mg-about 300 mg) of anIL-17 binding molecule; and b) thereafter administering: i) about 75mg-about 300 mg (e.g., about 150 mg-about 300 mg) of the IL-17 bindingmolecule to the patient monthly or ii) one dose of about 75 mg-about 300mg (e.g., about 150 mg-about 300 mg) of the IL-17 binding molecule tothe patient about one month following step a) and thereafteradministering at least one dose of about 75 mg-about 300 mg (e.g., about150 mg-about 300 mg) of the IL-17 binding molecule to the patient atstart of relapse.

Disclosed herein are methods of treating psoriasis, comprising: a)administering an IL-17 binding molecule to a patient in need thereofduring an induction regimen, wherein the induction regimen comprises aloading regimen that provides a mean maximum plasma concentration(C_(max)) of the IL-17 binding molecule of about 52 μg/ml-about 104μg/ml; and b) thereafter administering the IL-17 binding molecule to thepatient during a maintenance regimen that provides an averagesteady-state trough level of the IL-17 binding molecule between about 5μg/ml-about 70 μg/ml.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered to the patient during an induction regimen, wherein theinduction regimen comprises a loading regimen that provides a meanmaximum plasma concentration (C_(max)) of the IL-17 binding molecule ofabout 52 μg/ml-about 104 μg/ml; and b) thereafter, is to be administeredto the patient during a maintenance regimen that provides an averagesteady-state trough level of the IL-17 binding molecule between about 5μg/ml-about 70 μg/ml.

In some embodiments, the loading regimen provides a C_(max) of the IL-17binding molecule of about 52 μg/m at about day 32. In some embodiments,the maintenance regimen provides an average steady-state trough level ofthe IL-17 binding molecule of about 5 μg/ml-about 33 μg/ml. In someembodiments, the maintenance provides an average steady-state troughlevel of the IL-17 binding molecule of about 16 μg/ml. In someembodiments, the loading regimen provides a C_(max) of the IL-17 bindingmolecule of about 104 μg/m at about day 32. In some embodiments, themaintenance regimen provides an average steady-state trough level of theIL-17 binding molecule of about 11 μg/ml-about 70 μg/ml. In someembodiments, the maintenance regimen provides an average steady-statetrough level of the IL-17 binding molecule of about 33 μg/ml. In someembodiments, the induction regimen is twelve weeks. In some embodiments,the maintenance regimen employs monthly dosing of the IL-17 bindingmolecule.

Disclosed herein are methods of treating psoriasis, comprising: a)administering an IL-17 binding molecule to a patient in need thereofduring an induction regimen, wherein the induction regimen comprises aloading regimen that provides a mean trough level one month after thefourth dose of about 29.2 μg/ml; and b) thereafter administering theIL-17 binding molecule to the patient during a maintenance regimen thatprovides an average steady-state trough level of the IL-17 bindingmolecule of about 15 μg/ml.

Disclosed herein are IL-17 binding molecules for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered to the patient during an induction regimen, wherein theinduction regimen comprises a loading regimen that provides a meantrough level one month after the fourth dose of about 29.2 μg/ml; and b)thereafter, is to be administered to the patient during a maintenanceregimen that provides an average steady-state trough level of the IL-17binding molecule of about 15 μg/ml.

Combination Therapies for the Treatment of Psoriasis

In practicing the methods of treatment, regimens, or uses of the presentdisclosure, a therapeutically effective amount of an IL-17 antagonist,e.g., an IL-17 binding molecule (e.g., an IL-17 antibody, such assecukinumab) or and IL-17 receptor binding molecule, is administered toa subject, e.g., a mammal (e.g., a human). An IL-17 antagonist, e.g., anIL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab) orand IL-17 receptor binding molecule may be administered in accordancewith the method of the disclosure either alone or in combination withother therapies, such as, e.g., in combination with additional agentsand therapies for psoriasis. When coadministered with one or moreadditional agents, an IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or and IL-17 receptorbinding molecule may be administered either simultaneously with theother agent, or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering the IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or and IL-17 receptorbinding molecule in combination with other agents.

Various therapies may be beneficially combined with the disclosed IL-17antagonists, e.g., IL-17 binding molecules (e.g., an IL-17 antibody,such as secukinumab) and IL-17 receptor binding molecules, duringtreatment of psoriasis. Such therapies include topicals (over thecounter, non-steroidal compounds and steroidal compound), phototherapyand systemic treatment (e.g., with biologis or chemical entities).Non-limiting examples of topical agents for use with the disclosed IL-17antagonists, e.g., IL-17 binding molecules (e.g., an IL-17 antibody,such as secukinumab) and IL-17 receptor binding molecules, includesalicylic acid, coal tar, Dovonex® (calcipotriene), Taclonex®(calcipotriene and betamethasone dipropionate), Tazorec® (tazarotene),pimecrolimus, tacrolimus, Vectical® (calcitriol), Zithranol-RR®(anthralin) and topical steroids (e.g., corticosteroids). Examples ofphototherapy for use with the disclosed IL-17 antagonists, e.g., IL-17binding molecules (e.g., an IL-17 antibody, such as secukinumab) andIL-17 receptor binding molecules, includes treatment with psoralen+UVAor treatment with UVB (with or without tar). Examples of agents used insystemic treatment for use with the disclosed IL-17 antagonists, e.g.,IL-17 binding molecules (e.g., an IL-17 antibody, such as secukinumab)and IL-17 receptor binding molecules, include retionoids such asAcitretin (Soriatane®), cyclosporine, methotrexate, Hydrea®(hydroxyurea), isotretinoin, mycophenolate mofetil, mycophenolic acid,sulfasalazine, 6-thioguanine, fumarates (e.g, dimethylfumarate andfumaric acid esters), azathioprine, corticosteroids, leflunomide,tacrolimus, T-cell blockers (such as Amevive® (alefacept) and Raptiva®(efalizumab), tumor necrosis factor-alpha (TNF-alpha) blockers (such asEnbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab) andSimponi® (golimumab)) and interleukin 12/23 blockers (such as Stelara®(ustekinumab), tasocitinib, Efalizumab, and briakinumab.

Additional agents for use in combination with the disclosed IL-17antagonists, e.g., IL-17 binding molecules (e.g., an IL-17 antibody,such as secukinumab) and IL-17 receptor binding molecules, duringtreatment of psoriasis include apremilast, mometasome, voclosporin,Ketokonazol, Neuroskin Forte, recombinant human interleukin-10,voclosporin, VX-765, MED-1545, fluphenazine decanoate, acetomuinophn,bimosiamose cream, doxycycline, vancomycin, AbGn168, Vitamin D3,RO5310074, fludarabine Calcipotriol and hydrocortisone (LEO 80190),LE80185 (Taclonex® Scalp topical suspension/Xamiol® gel), Focetria(Monovalent MF59-Adjuvanted vaccine, tgAAC94 gene therapy vector,Apremilast, Capsaicin, Psirelax, ABT-874 (anti IL-12), IDEC-114,MEDI-522, INCB018424 phosphate cream, LE29102, BMS 587101, CD 2027,CRx-191, 8-methoxypsoralen or 5-methoxypsoralen, Bicillin L-A,LY2525623, INCB018424, LY2439821, CEP-701, CC-10004, certolizumab (CZP),GW786034 (pazopanib), doxycycline Curcuminoids C3 Complex, NYC 0462,RG3421, hOKT3gamma1(Ala-Ala), BT061, teplizumab, Chondroitin sulphate,CNTO 1275, monoclonal antibody to IL-12p40 and IL-23 p40 subunits,BMS-582949, MK0873, MEDI-507, M518101, ABT-874, AMG 827, AN2728, AMG714, AMG 139, PTH (1-34), U0267 Foam, CNTO 1275, QRX-101, CNTO 1959, LEO22811, Imiquimod, CTLA4Ig, Alga Dunaliella Bardawil, AS101 Cream,pioglitazone, pimecrolimus, ranibizumab, Zidovudine CDP870 (Certolizumabpegol), Onercept (r-hTBP-1), ACT-128800,4,4-dimethyl-benziso-2H-selenazine, CRx-191, CRx-197, doxercalciferol,LEO 19123 Cream (calcipotriol plus LEO 80122), LAS 41004, WBI-1001,tacrolimus, RAD001, rapamycin, rosiglitazone, pioglitazone, ABT-874,Aminopterin, AN2728, CD2027, ACT-128800, mometasone furoate, CT 327,clobetasol+LCD, BTT1023, E6201, topical vitamin B12, INCB018424Phosphate Cream, Xamiol gel, IP10.C8, BFH772, LEO 22811, Fluphenazine,MM-093, Clobex, SCH 527123, CF101, SRT2104, BIRT2584, CC10004,Tetrathiomolybdate, CP-690,550, U0267, ASP015K, VB-201, Acitretin (alsocalled U0279), RWJ-445380, Psoralait, Clobetasol propionate, botulinumtoxin type A, alefacept, erlotinib, BCT194, Ultravate Ointment,Roflumilast, CNTO 1275, halobetasol, CTA018 cream, ILV-094, COL-121,MEDI-507, AEB071. Additional agents for use in combination withsecukinumab during treatment of psoriasis include IL-6 antagonists, CD20antagonistis, CTLA4 antagnonists, IL-17 antagonists, IL-8 antagnoists,IL-21 antagonistis, IL-22 antagonist, VGEF antagnosits, CXCLantagonists, MMP antagonists, defensin antagonists, IL-1betaantagonists, and IL-23 antagonists (e.g., receptor decoys, antagonisticantibodies, etc.). A skilled artisan will be able to discern theappropriate dosages of the above agents for co-delivery with thedisclosed IL-17 antagonists, e.g., IL-17 binding molecules (e.g., anIL-17 antibody, such as secukinumab) and IL-17 receptor bindingmolecules.

Kits for the Treatment of Psoriasis

Provided herein are kits useful for providing IL-17 antagonists, e.g.,IL-17 binding molecules (e.g., an IL-17 antibody, such as secukinumab)and IL-17 receptor binding molecules, for the treatment of psoriasis.Such kits may comprise an IL-17 antagonist (e.g., in liquid orlyophilized form) or a pharmaceutical composition comprising the IL-17antagonist. Additionally, such kits may comprise means for administeringthe IL-17 binding molecule (e.g., a syringe or a prefilled pen) andinstructions for use. These kits may contain additional therapeuticagents (described supra) for treating psoriais, e.g., for delivery incombination with the enclosed IL-17 antagonists, e.g., secukinumab.

Accordingly, disclosed herein are kits comprising: a) a pharmaceuticalcomposition comprising a therapeutically effective amount of an IL-17binding molecule; b) means for administering the IL-17 antagonist (e.g.,IL-17 binding molecule or IL-17 receptor binding molecule) to a patienthaving psoriasis; and c) instructions providing: i) administering theIL-17 antagonist (e.g., IL-17 binding molecule or IL-17 receptor bindingmolecule) to the patient during an induction regimen comprising: a.administering about 75 mg-about 300 mg of the IL-17 antagonist (e.g.,IL-17 binding molecule or IL-17 receptor binding molecule) to thepatient weekly for five weeks, wherein the first dose of the IL-17binding molecule is administered during week zero; and b. thereafteradministering about 75 mg-about 300 mg of the IL-17 antagonist (e.g.,IL-17 binding molecule or IL-17 receptor binding molecule) to thepatient during week eight; and ii) administering the IL-17 antagonist(e.g., IL-17 binding molecule or IL-17 receptor binding molecule) to thepatient during a maintenance regimen comprising: a. administering about75 mg-about 300 mg of the IL-17 antagonist (e.g., IL-17 binding moleculeor IL-17 receptor binding molecule) to the patient each month, every twomonths or every three months; orb. administering at least one dose ofabout 75 mg-about 300 mg of the IL-17 antagonist (e.g., IL-17 bindingmolecule or IL-17 receptor binding molecule) to the patient at start ofrelapse.

General

In some embodiments of the disclosed methods, regimens, kits, uses, orpharmaceutical compositions, the IL-17 antagonist (e.g., IL-17 bindingmolecule or IL-17 receptor binding molecule) is selected from the groupconsisting of:

a) secukinumab;

b) an IL-17 antibody that binds to an epitope of IL-17 comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129;

c) an IL-17 antibody that binds to an epitope of IL-17 comprising Tyr43,Tyr44, Arg46, Ala79, Asp80;

d) an IL-17 antibody that binds to an epitope of an IL-17 homodimerhaving two mature IL-17 protein chains, said epitope comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the otherchain;

e) an IL-17 antibody that binds to an epitope of an IL-17 homodimerhaving two mature IL-17 protein chains, said epitope comprising Leu74,Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128,His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the otherchain, wherein the IL-17 binding molecule has a K_(D) of about 100-200pM, and wherein the IL-17 binding molecule has an in vivo half-life ofabout 4 weeks; and

f) an IL-17 antibody that comprises an antibody selected from the groupconsisting of:

-   -   i) an immunoglobulin heavy chain variable domain (V_(H))        comprising the amino acid sequence set forth as SEQ ID NO:8;    -   ii) an immunoglobulin light chain variable domain (V_(L))        comprising the amino acid sequence set forth as SEQ ID NO:10;    -   iii) an immunoglobulin V_(H) domain comprising the amino acid        sequence set forth as SEQ ID NO:8 and an immunoglobulin V_(L)        domain comprising the amino acid sequence set forth as SEQ ID        NO:10;    -   iv) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3;    -   v) an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;    -   vi) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID        NO:13;    -   vii) an immunoglobulin V_(H) domain comprising the hypervariable        regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3        and an immunoglobulin V_(L) domain comprising the hypervariable        regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;        and    -   viii) an immunoglobulin V_(H) domain comprising the        hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12        and SEQ ID NO:13 and an immunoglobulin V_(L) domain comprising        the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5        and SEQ ID NO:6.

In the above mentioned methods, therapeutic regimens, uses,pharmaceutical compositions, combinations, combination therapies, andkits, a preferred embodiment employs a human IL-17 antibody, e.g., ahuman IL-17 antibody (e.g., a human monoclonal antibody), mostpreferably secukinumab.

In some embodiments of the disclosed methods, regimens, kits, IL-17binding molecules, uses and pharmaceutical compositions, the the IL-17antagonist (e.g., IL-17 binding molecule or IL-17 receptor bindingmolecule) is self-administered by the patient.

In some of the above mentioned methods, therapeutic regimens, uses,pharmaceutical compositions, combinations, combination therapies, andkits, the patient to be treated with secukinumab is a naïve patient(i.e., has not been previously treated for psoriasis). In otherembodiments, the patient to be treated with secukinumab has beenpreviously treated with a systemic agent for psoriasis, e.g., with anagent selected from the group consisting of methotrexate, cyclosporine,fumaric acid esters, acitretin, alefacept, adalimumab, efalizumab,etanercept, infliximab, golimumab or ustekinumab. In preferredembodiments, the systemic agent is methotrexate.

In some embodiments, the disclosed treatment regimens are used inpatients having moderate to severe chronic plaque psoriasis who arecandidates for systemic therapy or phototherapy. In some embodiments,the disclosed treatment regimens are used in patients having moderate tosevere chronic plaque psoriasis who are candidates for systemic therapyor phototherapy, and when other systemic therapies are medically lessappropriate. In some embodiments, the disclosed treatment regimens areused in patients having moderate to severe chronic plaque psoriasis whoare candidates for systemic therapy, and when other systemic therapiesare medically less appropriate. In some embodiments, the patient may bean anti-TNF alpha psoriasis treatment non-responsder, partial responder(e.g, an inadequate responder), relapser or rebounder.

In some of the above mentioned methods, therapeutic regimens, uses,pharmaceutical compositions, combinations, combination therapies, andkits, start of relapse is defined as: a) the loss of at least 20% (⅕) ofthe maximum PASI response achieved at any time before the visit at whichthe assessment of start or relapse is made; and b) loss of PASI75.

In some of the above mentioned methods, therapeutic regimens, uses,pharmaceutical compositions, combinations, combination therapies, andkits, the patient suffers from psoriasis of the palms and/or soles, facepsoriasis, scalp psoriasis, genital psoriasis, inverse psoriasis, ornail psoriasis. In further embodiments, the psoriasis is chronicplaque-type psoriasis.

EXAMPLES Example 1—Proof of Concept Using Secukinumab to Treat Psoriasis

In a completed proof of concept (PoC) study (CAIN457A2102), the effectsof secukinumab administered at 3 mg/kg as a single intravenous infusionwere compared with that of placebo in thirty-six patients with activechronic plaque type psoriasis. The study demonstrated efficacy at the4-week endpoint and continuous efficacy at 12 weeks based on PsoriasisArea an Severity Index (PAST) and Investigator Global Assessment (IGA)endpoints.

In a follow up (CAIN457A2212) study, three secukinumab i.v. regimenswere tested in patients with active chronic plaque-type psoriasis: 1×3mg/kg (administered on day 1), 1×10 mg/kg (administered on day 1), and3×10 mg/kg (administered on days 1, 15, and 29). The 3 mg/kg i.v. armconfirmed the efficacy seen in PoC (40% of patients achieving PASI75after 12 wks). The 10 mg/kg i.v. arms displayed much improved efficacycompared to 3 mg/kg i.v. treatment arm, with 73% (10 mg/kg)-87% (3×10mg/kg) patients achieve PASI75 at week 12. Moreover, the onset of actionof secukinumab was very fast (about 2 weeks). Notably, as shown in FIG.1, no rebound is observed in secukinumab-treated patients within 8 weeksafter dosing. This is in contrast to various other psoriasis treatments,which have been shown to induce rebound in patients, e.g., some TNFalpha antagonists and cyclosporin. This lack of rebound suggests thefeasibility of intermittent psoriasis treatment, e.g., treatment at SoR,with secukinumab.

Example 2—Study CAIN457A2211 Example 2.1—Protocol Primary Objectives

To evaluate the efficacy of three induction regimens of secukinumabadministered subcutaneously in patients with moderate to severe chronicplaque-type psoriasis with respect to PASI 75 achievement after 12 weeksof treatment, compared to placebo.

Study Design

This multicenter study uses a parallel-group, randomized, double-blinddesign. A graphical illustration of the study is shown in FIG. 2. Thestudy consists of 4 periods: the screening period, the induction period,the maintenance period and the follow-up period. The screening period of4 weeks will be used to assess eligibility and to taper patients offdisallowed medications. At the baseline visit, eligible patients will berandomized to one of the induction treatment arms. Randomization will bestratified according to body weight 90 kg or <90 kg). Patients will berandomized as follows:

Induction Period

Patients will be assigned to one of the following four inductiontreatment arms in a ratio of 1:2:2:1 respectively:

-   -   Induction with single injection—“Single”: secukinumab 150 mg        s.c. administered at week 1    -   Induction with monthly injections—“Monthly”: secukinumab 150 mg        s.c. administered at weeks 1, 5, 9    -   Early loading induction—“Early”: secukinumab 150 mg s.c.        administered at weeks 1, 2, 3, 5    -   Placebo—“Placebo”: Placebo administered at weeks 1, 2, 3, 5, 9        In each of the active treatment arms, placebo injections will be        administered to maintain the blind in the study.

Maintenance Period

At week 13, patients will be classified as responders (achieving atleast PASI 75), partial responders (achieving PASI 50, but not PASI 75)or non-responders (not achieving PASI 50). Responders at week 13 will befurther randomized to one of the following maintenance treatment arms ina ratio of 1:1:

-   -   Fixed-time interval regimen—“FI”: secukinumab 150 mg s.c.        administered at week 13 and at week 25 and placebo at regular        scheduled visit at which a start of relapse is observed.    -   Treatment at start of relapse regimen—“SR”: Placebo administered        at week 13 and possibly at week 25 if no start of relapse        observed, and secukinumab 150 mg s.c. administered at regular        scheduled visit at which a start of relapse is observed.

Responders on placebo regimen will remain on the placebo arm and willreceive placebo at week 13 and at week 25 and placebo at regularscheduled visit at which a start of relapse is observed.

Open Label Phase

Non responders and partial responders at week 13 and patients whoexperience 2 consecutive relapses at scheduled visits from week 13onwards will be eligible to enter the open label phase—“OL”: secukinumab150 mg s.c. administered every 4 weeks. The last study drugadministration for all patients remaining in the study will potentiallybe at week 33. All randomized patients will enter the treatment-freefollow-up period 4 weeks after the last study drug administration tomonitor safety and will be monitored for 12 weeks (Visits 13, 14 and15). The assessment to address the primary objective will be performedat the end of the induction period (week 13).

Psoriasis Area and Severity Index: PASI

A PASI score will be derived at scheduled visits. In the PASI scoringsystem, the head, trunk, upper limbs and lower limbs are assessedseparately for erythema, thickening (plaque elevation, induration), andscaling (desquamation) (see Table 1).

Example 2.2—Results for CAIN457A2211 Interim Analysis Results (12Weeks):

PASI Response

Data available from the interim analysis performed at week 12 shows aPASI75 of 12% in the “Single” arm, 43% in the “Monthly” arm and 55% inthe “Early” arm compared to 5% in the placebo arm (Table 6 and FIG. 3).Both “Monthly” and “Early” arms showed statistical significance comparedto placebo (p<0.001). The “Early” arm (4×150 mg secukinumab s.c. withinthe first five weeks) showed the highest efficacy, which was better than3 mg/kg IV (PoC), but lower than 10 mg/kg IV (CAIN457A2212).

TABLE 6 PASI achievement after 12 weeks of treatment with secukinumabcompared to placebo in both “Monthly” and “Early” arms (p <0.001) instudy CAIN457A2211. Treatment Group PASI 50 PASI 75 PASI 90 secukinumab150 mg × 1 28.8% 12.1%  4.5% (“Single”; N = 66) secukinumab 150 mg × 360.9% 42.8% 18.1% (“Monthly”; N = 138) secukinumab 150 mg × 4 76.5%54.5% 31.8% (“Early”; N = 133) Placebo (N = 67) 13.6%  4.5%  4.5%

In study CAIN457A2211, response rates did not meaningfully improve afterWeek 8 in the “Early” arm (which did not include dosing at Week 8),whereas the response rate clearly improved after Week 8 in the “Monthly”arm (which did include dosing at Week 8) (FIG. 3). Moreover, 8 patientsin the “Early” arm who had already achieved a PASI 75 response at Week 8had lost the PASI 75 by Week 12. This data supports monthly dosing afterweekly loading.

A body-weight-response relationship was also shown in studyCAIN457A2211; 60.9% of patients with a body weight of <90 kg showed aPASI 75 response after twelve weeks of treatment, whereas only 47.6%achieved this response in the group of patients weighing ≥90 kg (Table7). The response rate for achievement of an Investigator's GlobalAssessment (IGA) score or 0 or 1 was also statistically significantlybetter for the “Monthly” (22.6%) and “Early” (37.9%) arms, when comparedto placebo (3.0%; p<0.001). The short term safety profile of secukinumabin this study was comparable to placebo without a dose effect seen and asimilar percentage (˜60-70%) of adverse events across all dose arms andplacebo. This included infectious events which were 21%, 39%, 33% in the“single”, “monthly” and “early” cohorts respectively compared to 37% inthe placebo cohort. Percentage of serious adverse events (SAEs) were 5%,2%, 5% in the “single”, “monthly” and “early” cohorts respectivelycompared to 3% in the placebo cohort.

TABLE 7 PASI achievement analyzed by weight after 12 weeks of treatmentwith secukinumab compared to placebo. Treatment Group <90 kg ≥90 kg Allsecukinumab 150 mg × 1 20.6% (7/34) 3.1% (1/32) 12.1% (“Single”; N = 66)secukinumab 150 mg × 3 53.6% (37/69) 31.9% (22/69) 42.8% (“Monthly”; N =138) secukinumab 150 mg × 4 60.9% (42/69) 47.6% (30/63) 54.5% (“Early”;N = 133) Placebo 5.9% (2/34) 3.1% (1/32)  4.5% (N = 67)

IGA Response

In addition to the PASI response, the primary endpoint analysis wasperformed on the Investigator's Global Assessment (IGA) achievement. Ascale from 0 (clear) to 5 (very severe) was used. A patient was regardedas an IGA responder if an IGA of 0 (clear) or 1 (almost clear) wasreached; an inclusion criterion was a baseline IGA of ≥3. After twelveweeks of treatment, an IGA response was achieved by 4.5% of the patientsin the “Single” arm, 22.6% of the patients in the “Monthly” arm, and37.9% in the “Early” arm; only 3.0% of patients in the placebo armachieved an IGA 0/1 response.

Just as for the PASI response over time, it was shown that the number ofIGA responders increased after administration of secukinumab after eightweeks in the “Monthly” arm, but only slightly so in the “Early” arm, inwhich no secukinumab was given after eight weeks. Furthermore, a bodyweight-IGA response relationship was also shown for the “Single” and the“Monthly” regimen, but not for the “Early” regimen. In the “Single” arm,the IGA response rate after twelve weeks of treatment was 8.8% in theweight group of <90 kg, but 0.0% in the weight group ≥90 kg. Similarly,in the “Monthly” arm, the response rates were 35.3% and 10.1%. In the“Early” arm, the response rates were very similar between body weightgroups, with 39.1% (<90 kg) and 36.5% (≥90 kg).

Interim Analysis Results (28 Weeks):

An interim analysis (IA) was performed 16 weeks after 103 patients hadreached a PASI 75 response after twelve weeks of treatment. In this IA,the key secondary objective of comparing the two maintenance regimens(“fixed interval” and “treatment at start of relapse”) was assessed byan internal Data Monitoring Committee (DMC).

Baseline Demographics

Compared to the demographics at randomization, the population in thisinterim analysis consisted of patients with a lower mean body weight(85.1 kg compared to 93.1 kg at randomization). Otherwise, thedemographics were comparable. The difference in mean body weight wasexpected, as only responders entered the double blind maintenanceperiod, and a lower body weight is associated with a higher probabilityof showing a response after treatment with secukinumab.

PASI Response

In the “fixed interval” treatment arm (51 patients; maintenancetreatment with 150 mg of secukinumab s.c. twelve and twenty-four weeksafter randomization), 94.1% of patients showed a PASI 75 response (lossof 5.9% response) four weeks into maintenance, 80.4% after eight weeks(loss of 19.6%), and 66.7% twelve weeks into the maintenance period(loss of 33.3%) (FIGS. 4A and 4B). At the Week 25 visit, patients werere-treated with secukinumab, and four weeks later, the percentage ofpatients with a PASI 75 response slightly increased to 68.6%.

In addition, the fixed interval of four weeks was tested in the openlabel part of study CAIN457A2211. By definition, the patients whoentered this part of the study did not have a PASI 75 response at Week12. When treated with secukinumab 150 mg open label every four weeks, asignificant percentage of patients converted to responder status withineight to twelve weeks (Table 8). To support the rationale of amaintenance interval of four weeks, it should be noted that once acertain level of PASI 75 response rate is achieved (“Single” and“Monthly”: Week 20; “Early” and Placebo: Week 24), this percentage iskept at the same level or is slightly improved with this regimen. Thesafety analysis of the patients in the open label arm of studyCAIN457A2211, during which patients were treated with 150 mg ofsecukinumab every four weeks, reveals no clinically meaningfuldifference between the open label arm and the other treatment regimens(i.e. fixed interval=treatment every 12 weeks, and re-treatment at startof relapse). This supports the assumption that treatment withsecukinumab in maintenance every four weeks promises to show anacceptable safety profile.

TABLE 8 Observed PASI 75 response rates of patients in the open labelarm of study CAIN457A2211 receiving 150 mg s.c. every 4 weeks after 12weeks. Shown in the table are the patients that provided data up to Week28 in the open label arm for the interim analysis of study CAIN457A2211.Induction treatment up to Week 12 Single Monthly Early Placebo Week (n =54) (n = 78) (n = 57) (n = 58) 12  0.0%  0.0%  0.0%  0.0% 16 14.8% 19.2%19.3% 15.5% 20 35.2% 26.9% 19.3% 39.7% 24 40.7% 28.2% 31.6% 55.2% 2842.6% 29.5% 29.8% 60.3%

In addition, the time until patients suffered from a “start of relapse”(in the CAIN457A2211 study: this was defined as loss of at least 33% ofthe PASI gain achieved before, where PASI gain was PASI score atrandomization minus the lowest PASI ever achieved during the study) wasassessed. In the “start of relapse” arm (in which patients were onlyretreated if they suffered from a “start of relapse”), the first “startof relapse” observations were made thirteen weeks after last study drugadministration (6.0% of patients). At sixteen weeks after last studydrug administration, only 28.5% of patients experienced a “start ofrelapse”, 41.4% at Week 20, and 55.6% at Week 24 (FIG. 4A, dashed line).

IGA Response

At the beginning of the maintenance period (i.e., twelve weeks afterstart of study drug), 64.7% of patients in the “fixed interval” armshowed an IGA 0 (“clear”) or 1 (“almost clear”) response. Four weeksinto maintenance, this response was shown by 70.6% of patients, and ateight weeks by 60.8% of the patients. Twelve weeks into the maintenanceperiod, before the patients were retreated for the first time inmaintenance, 52.9% of patients had an IGA 0/1 response, and this levelwas kept four weeks later (51.0%).

Discussion and Analysis

An internal Primary Endpoint Analysis (PEA) was performed after allpatients had reached twelve weeks of treatment. The results confirmedthat secukinumab is efficacious in the studied indication, meeting theprimary endpoint of showing the effect of secukinumab with regard toPASI 75 achievement after twelve weeks of treatment, compared toplacebo, in the “Monthly” and “Early” arms.

An Interim Analysis was performed on 103 patients that were respondersafter twelve weeks of treatment. The key secondary endpoint of comparingthe two maintenance regimens (“fixed interval” and “treatment at startof relapse”) was assessed by an internal Data Monitoring Committee(DMC). Considering that the treatment goal during maintenance in a“fixed interval” regimen is to keep patients in a status of PASI 75response, the interim analysis showed that the revised fixed treatmentinterval should be four weeks. This regimen is used in all phase IIIstudies analyzing fixed dosing.

The interpretation of the maintenance information from studyCAIN457A2211 showed that to keep most patients in a PASI 75 response, afixed treatment interval of four weeks is required (FIG. 4). However,66.7% of patients kept their PASI 75 response until 12 weeks after lastadministration of secukinumab, and therefore might not necessarily needre-treatment earlier than at this time point (FIGS. 4A and B). Theanalysis of the re-treatment at start of relapse approach shows thatsome patients might be successfully re-treated at longer intervals. FIG.5 presents the number of subjects with start of relapse over time, andshows that even after about 6 months following last secukinumabadministration, a significant percentage of patients maintain ameaningful clinical response. These data imply that an individualizedmaintenance treatment approach could be useful for the treatment ofpsoriasis with secukinumab. While not all patients would be eligible forsuch an approach (i.e., because of their individual response/relapsebehavior, because of the need for close monitoring of symptoms, orbecause of the need to reach the physician on short notice), and mighttherefore prefer a fixed interval treatment regimen, some patients areexpected to benefit from individualized therapy. Patients with a needfor less frequent injections than every four weeks would be exposed toless drug compared to a regimen with fixed intervals, which is regardedas a safety benefit.

The analysis of the maintenance period of study CAIN457A2211, whileshowing the feasibility and potential benefit of the individualizedtreatment approach, also shows that the rules for “re-treatment at startof relapse” can be refined to achieve greater disease control. Thereforeboth the starting as well as the stopping rule for re-treatment at startof relapse has been modified for phase III in order to maximize andmaintain ideal disease control: start of relapse in phase III is definedas a loss of 20% of the previous PASI gain (as opposed to 33% in phaseII) and a loss of PASI 75 response. In addition, once re-treatment atstart of relapse has been initiated, it will be continued with a singleadministration of secukinumab every four weeks until a PASI75 responsehas been reached again.

Example 3—Study A2220 Example 3.1—Protocol

Primary Objective

To assess the efficacy of three different doses of secukinumab s.c.administered monthly (25 mg, 75 mg and 150 mg) or as a singleadministration (25 mg) in patients with moderate to severe chronicplaque-type psoriasis with respect to PASI 75 achievement 12 weeks afterstart of treatment, compared to placebo.

Study Design

This is a multicenter, randomized, double-blind, placebo-controlled,parallel-group trial in 120 patients with moderate to severe chronicplaque-type psoriasis. It is expected that patients will be enrolled ataround 25 study sites, whereas a site should recruit no less than 5patients.

The study consists of 3 periods: screening, treatment and follow up. Agraphical representation of the study design is shown in FIG. 6.

The screening period of up to 4 weeks will be used to assess eligibilityof the patients and taper patients off disallowed medications. Theeligible patients will be randomized into one of five treatment groups,and will receive the study medication monthly three times (weeks 1, 5,and 9). Either placebo or one of three different doses as two differentregimens of secukinumab will be administered to the patients of eachtreatment group with a randomization ratio of 1:1:1:1:1. Randomizationwill be stratified according to body weight (<90 kg or ≥90 kg). Duringthe treatment period, patients will be visiting the site at weeks 2, 3,5 and 9. At weeks 5 and 9 they will receive study drug. At all visits,safety, efficacy and PK assessments will be performed. At the end of the12 week treatment period, patients will enter a follow-up period ofmaximally 24 weeks. If the patient requires other systemic psoriasistreatment or phototherapy before the end of the follow-up, an end ofstudy visit should be preformed.

The primary endpoint (i.e. achievement of PASI 75 12 weeks after startof treatment) will be analyzed once all patients have completed thetreatment phase.

Rationale of Study Design

This study will provide dose ranging information for a treatment periodof 12 weeks (with last study drug administration at week 9). The purposeof the present study is to determine the dose(s) of secukinumab thatreduce(s) the severity of psoriasis symptoms (compared to placebo).

The study is designed to investigate whether there is a reduction ofpsoriasis symptoms' severity as measured by Psoriasis Area and SeverityIndex (PAST) and Investigator's Global Assessment (IGA) achievement inpatients with moderate to severe plaque type psoriasis 12 weeks afterstart of treatment with secukinumab. The PASI score, the assessment ofthe severity of the psoriasis symptoms and the extent to which thepatient's body area is affected by the disease, is considered acceptableby health authorities to assess efficacy in conjunction withInvestigator's Global Assessment (IGA).

Treatment Arms

Patients will be assigned to one of the following 5 treatment arms in aratio of 1:1:1:1:1, with 24 patients per arm

-   -   Arm “3×150 mg”: secukinumab 150 mg s.c. administered at weeks 1,        5, and 9    -   Arm “3×75 mg”: secukinumab 75 mg s.c. administered at weeks 1,        5, and 9    -   Arm “3×25 mg”: secukinumab 25 mg s.c. administered at weeks 1,        5, and 9    -   Arm “1×25 mg”: secukinumab 25 mg s.c. administered at week 1,        and placebo s.c. administered at weeks 5 and 9    -   Arm “Placebo”: Placebo s.c. administered at weeks 1, 5, and 9

Psoriasis Area and Severity Index: PASI

A PASI score will be derived at scheduled visits. In the PASI scoringsystem, the head, trunk, upper limbs and lower limbs are assessedseparately for erythema, thickening (plaque elevation, induration), andscaling (desquamation) (see Table 1).

Example 3.2—CAIN457A2220 Study Results (Week 12)

PASI Response

Results of the PASI 75 (primary variable), PASI 50 and PASI 90 responsesare shown in FIG. 7 and summarized in Table 9. Highest responses wereseen in the 3×150 mg cohort with a PASI 75 of 81.5% (p<0.001 vs.placebo) and a PASI 90 of 51.9% (p<0.001 vs. placebo). The 3×75 mgcohort had a PASI 75 of 57.1% (p=0.002 vs. placebo) after 12 weeks oftreatment. Thus, a clear dose-response relationship between cohorts canbe seen for all cohorts except the 1×25 mg group, which was notstatistically different from placebo (i.e., the 1×25 mg at 3.4%(p=0.308) and the 3×25 mg cohort at 19.2% (p=0.362) showed nostatistically significant difference when compared to placebo (Table10)). Notably, PASI 90 was only achieved by 19% of patients in the 3×75mg cohort and 7.7% in the 3×25 mg cohort. Response rates were very lowin the 1×25 mg cohort with none of the patients achieving PASI 90.Placebo response rates were 9.1% (2 of 22 patients) for PASI 75 and 4.5%(1 of 22 patients) for PASI 90. In the subgroup analyses (Table 10), thehighest PASI 75 (93.8%) response was seen in patients treated with 3×150mg and weighing less than 90 kg, whereas only 63.6% of patients weighingmore than 90 kg achieved a PASI 75 in this cohort after 12 weeks oftreatment.

TABLE 9 Number (%) of subjects achieving PASI 50, PASI 75, or PASI 90 byvisit and treatment (full analysis set, LOCF). 1 × 25 mg 3 × 25 mg 3 ×75 mg 3 × 150 mg Placebo N = 29 N = 26 N = 21 N = 27 N = 22 VisitCriterion n (%) n (%) n (%) n (%) n (%) Week 2 n evaluable 29 26 21 2722 PASI 50 1 (3.4) 2 (7.7) 1 (4.8)  3 (11.1) 0 (0.0) PASI 75 0 (0.0) 0(0.0) 0 (0.0) 0 (0.0) 0 (0.0) PASI 90 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0(0.0) Week 3 n evaluable 29 26 21 27 22 PASI 50 1 (3.4) 2 (7.7)  5(23.8)  5 (18.5) 1 (4.5) PASI 75 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)PASI 90 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Week 5 n evaluable 29 2621 27 22 PASI 50  3 (10.3)  4 (15.4)  6 (28.6) 13 (48.1) 1 (4.5) PASI 750 (0.0) 2 (7.7) 1 (4.8)  4 (14.8) 1 (4.5) PASI 90 0 (0.0) 0 (0.0) 0(0.0) 1 (3.7) 0 (0.0) Week 9 n evaluable 29 26 21 27 22 PASI 50  3(10.3) 10 (38.5) 11 (52.4) 23 (85.2)  3 (13.6) PASI 75 1 (3.4)  3 (11.5) 7 (33.3) 18 (66.7) 2 (9.1) PASI 90 0 (0.0) 1 (3.8) 2 (9.5)  4 (14.8) 0(0.0) Week 13 n evaluable 29 26 21 27 22 PASI 50  5 (17.2) 15 (57.7) 17(81.0) 23 (85.2)  4 (18.2) PASI 75 1 (3.4)  5 (19.2) 12 (57.1) 22 (81.5)2 (9.1) PASI 90 0 (0.0) 2 (7.7)  4 (19.0) 14 (51.9) 1 (4.5) Percentagesare based on the number of subjects with evaluable data (n evaluable).

TABLE 10 Subgroup analysis: Number (%) of subjects achieving PAST 75 atWeek 13, by treatment, by body weight group (full analysis set, LOCF).Subgroup 1 × 25 mg 3 × 25 mg 3 × 75 mg 3 × 150 mg Placebo Weight N = 29N = 26 N = 21 N = 27 N = 22 Stratum Criterion n (%) n (%) n (%) n (%) n(%) All Patients n evaluable 29 26 21 27 22 Overall PAST 75 Achievement1 (3.4) 5 (19.2) 12 (57.1) 22 (81.5) 2 (9.1)  <90 kg n evaluable 16 1312 16 10 PAST 75 Achievement 1 (6.3) 5 (38.5)  7 (58.3) 15 (93.8) 2(20.0) >=90 kg n evaluable 13 13 9 11 12 PAST 75 Achievement 0 (0.0) 0(0.0)   5 (55.6)  7 (63.6) 0 (0.0) 

Discussion and Analysis

The results of this 12 week dose finding study further confirm theefficacy of secukinumab in chronic plaque-type psoriasis. Secukinumab150 mg given s.c. monthly for 3 doses resulted in PASI 75 and PASI 90response rates of 81.5% and 51.9%, respectively (Table 9). Theseresponse rates were higher than those observed in the highest responsecohort in study A2211, the “Early” arm, where patients received 4×secukinumab 150 mg s.c. (at Baseline, Week 1, Week 2, and Week 4).

The data from the primary endpoint analysis of this study clearly implythat the clinical effect of a single injection of secukinumab 25 mg s.c.is similar to placebo. Although responses in the 3×25 mg cohort arenumerically slightly higher than placebo, they show no statisticalsignificance vs. placebo. Both the 3×75 mg and the 3×150 mg cohorts showgood PASI 75 responses. However, only the 3×150 mg cohort achieves PASI90 responses in excess of 50% at 12 weeks.

As has been observed in some of the dosing regimens for studyCAIN457A2211, there is an effect of body weight on response totreatment, with subjects weighing less than 90 kg having markedly higherPASI 75 response rates (Table 10). Although this effect of weight isseen in most dose cohorts, the difference in response between patients<90 kg vs. ≥90 kg in the 1×25 mg and 3×25 mg is not much different fromplacebo. This is further indication that these low doses offer noclinically meaningful benefit.

In summary, CAIN457A2220 achieved the objective of definingnon-effective dose regimens of secukinumab (1×25 mg, and 3×25 mg) inpsoriasis and demonstrates that in order to attain a good PASI 75response at Week 12, at least 3×150 mg is required. As seen in othertrials of secukinumab in psoriasis, this study confirmed that there wasan effect of body weight on clinical response rates using the doseregimens assessed.

Example 4—Modelling and Simulation—Improved Induction and MaintenanceRegimens Example 4.3—Modeling Studies

The relationship between secukinumab dose/regimen, secukinumab plasmaconcentration and the PASI response relationship has been modeled usinga population-PK/PD approach. The model has been built incrementallybuilt and updated based on data from the studies CAIN457A2102,CAIN457A2103, CAIN457A2211, CAIN457A2212, and CAIN457A2220.

Studies CAIN457A2102 and CAIN457A2212 are described in Example 1; studyCAIN457A2211 is described in Example 2. Study CAIN457A2220 is describedin Example 3. Study CAIN457A2103 assessed the absolute bioavailabilityof secukinumab after subcutaneous administration. Fourteen patients withmoderate to severe chronic plaque-type psoriasis were randomized toreceive either a subcutaneous (150 mg, n=7) or intravenous (1 mg/kg,n=7) administration of secukinumab at day 1. The second study drugadministration at day 29 occurred via the reversed route. Patients werefollowed up for 12 weeks after last dose. Local tolerability ofsubcutaneously administered secukinumab was excellent with no evidenceof patient reported pain, or physician reported injection sitereactions. Bioavailability of subcutaneously administered secukinumabwas approximately 60% compared to the intravenous administration. Theresults supported the subcutaneous administration of secukinumab.

Concentration profiles of secukinumab are described by a two-compartmentmodel, with combined first-order absorption to reflect subcutaneousadministration and zero-order absorption to reflect intravenousadministration. PASI profiles are characterized by a turnover (indirectresponse) model. The drug effect acts on the turnover model via anEmax-function, driven by secukinumab concentration in the centralcompartment. Inter-individual variability is estimated as a randomeffect on PK parameters (clearance, volume of distribution,inter-compartmental clearance, volume of distribution of peripheralcompartment, bioavailability, and absorption rate), and PD parameters(turnover out-rate kout, PASI steady state level, and EC₅₀).

Based on this model and the final parameter estimates, simulations wererun to predict the expected outcome for the proposed dosing regimen.Uncertainty of fixed effects, as well as random effects varianceparameters is taken into account, by sampling new parameter sets persimulation replicate. Model-validation was performed using standardassessment methods (goodness-of-fit analysis, predictive checks, andexternal validation based on prospective predictions).

Example 4.3—Results of Modeling Studies

While 300 mg secukinumab s.c. was not tested in the phase II studies inpsoriasis (although it was tested in rheumatoid arthritis), patientswere exposed to higher doses (up to 3×10 mg/kg i.v.) in the psoriasisstudy CAIN457A2212. As FIG. 8 demonstrates, the proposed loading regimenwith 150 mg and 300 mg s.c. will lead to a lower exposure compared tostudy CAIN457A2212. More specifically, the proposed dose regimen of 300mg s.c. delivers a similar exposure profile to 10 mg/kg i.v. whileavoiding high exposure peaks, and is projected to lead to PASI 75response rates similar to those seen with 10 mg/kg i.v. Thus,CAIN457A2304 proceeds with s.c. loading regimens using 150 mg and 300 mgdoses.

The proposed induction regimen is supported by additional model-basedanalyses using data from four psoriasis studies (CAIN457A2102,CAIN457A2211, CAIN457A2212, and CAIN457A2220). As seen in FIG. 9, theproposed induction regimen (weekly for five weeks during weeks 1, 2, 3,4, and 5, followed by an additional induction dose at week 9) ispredicted to deliver a notably better PASI 75 response rate after twelveweeks of treatment when compared to the response rates observed in studyCAIN457A2211. The predicted efficacy of a 75 mg dose regimen depicted inFIG. 9 is not ideal.

The proposed maintenance regimen is also supported by model-basedanalyses. Fixed treatment intervals of four, eight and twelve weeks havebeen simulated for the 150 mg dose, with the results shown in FIG. 10.It can be seen that only the four week interval effectively maintains aPASI 75 response in most patients.

Example 5—Study CAIN457A2304

Study CAIN457A2304 is planned to be a randomized, double-blind,multicenter study of subcutaneous secukinumab, in either afixed-interval or a treatment-at-start-of-relapse maintenance regimen,to demonstrate the efficacy on Psoriasis Area and Severity Index (PAST)and on Investigator's Global Assessment (IGA) score and to assess thesafety and tolerability up to one year in patients with moderate tosevere chronic plaque-type psoriasis.

After a screening period of up to four weeks, about 918 patients will berandomized to receive secukinumab in one of two different doses (150 mgor 300 mg). Secukinumab will be administered at Weeks 0, 1, 2, 3, 4, and8 during the induction phase. At the end of the induction phase,patients who have shown a PASI 75 response after twelve weeks oftreatment will be randomized to either receive secukinumab every fourweeks (two different doses i.e. 150 mg or 300 mg), starting at Week 12,and up until Week 48 (for an overall treatment duration of 52 weeks); orto receive secukinumab in an individualized treatment regimen. In theindividualized regimen, patients will only receive secukinumab when theysuffer from a start of relapse (defined as a loss of at least 20% of themaximal PASI gain achieved previously, and a loss of PASI 75 response);they will then continue to receive secukinumab every four weeks untilthey have achieved a PASI 75 response, after which they will go offtreatment again. The individual doses will be equivalent to the dosesthe patients had received and responded to during the induction period(i.e. 150 mg or 300 mg). A graphical illustration of the study is shownin FIG. 11.

As the primary objective of this study CAIN457A2304 is to compare twodifferent maintenance regimens, and as only very few placebo patientswould be expected to enter the maintenance part of the study (i.e.beyond the first twelve weeks of treatment), the study does not containa placebo group. After the end of the maintenance treatment period,patients will be eligible to enter the extension trial CAIN457A2304E1,or enter a follow-up period of twelve weeks after last study drugadministration.

The extension study of CAIN457A2304 (CAIN457A2304E1) is planned to be arandomized, double-blind, multicenter study of subcutaneous secukinumab,in either a fixed-interval or a treatment-at-start-of-relapsemaintenance regimen, to demonstrate the efficacy on Psoriasis Area andSeverity Index (PAST) and on Investigator's Global Assessment (IGA)score and to assess the safety and tolerability for an additional yearin patients with moderate to severe chronic plaque-type psoriasis.

Patients who have participated in study CAIN457A2304 and have completedthe maintenance treatment period of the respective study will beeligible to enter this extension trial. Patients will remain on the dose(i.e. either 150 mg or 300 mg of secukinumab) and regimen (i.e. either“dosing at fixed intervals” or “dosing at start of relapse”) that theyreceived during the core study. The treatment duration of the extensionstudy is currently planned to be at least 52 weeks.

Example 6—Pharmokinetic (PK) Information for Seckukinumab

Based on data obtained from various studies, including those discussedin the above Examples, the following PK information is provided forseckukinumab (Table 11).

TABLE 11 Pharmokinetic values for secukinumab. Experimental PK valuesare compiled from various secukinumab psoriasis trials. Simulated valuesare provided for the indicated psoriasis dosing regimens. ExperimentalInduction mean trough level one month after a 4^(th) dose of 150 mgdelivered s.c. at weeks 0, 1, 2 and 4~29.2 μg/mL, with a 30-40%inter-patient variation Maintenance average steady-state trough levels~15 μg/ml (for a monthly 150 mg regimen), with a 30-40% inter-patientvariation Simulated Induction (150 or 300 mg delivered s.c. weeks 0, 1,2, 3, 4, and 8) C_(max) (around 32 days) for a typical 90 kg patient:~52 μg/ml (for 150 mg regimen) ~104 μg/ml (for 300 mg regimen)Maintenance (150 or 300 mg delivered s.c. monthly beginning week 12)Average steady-state trough levels for a typical 90 kg psoriasispatient: ~16 μg/ml (for a monthly 150 mg regimen) ~33 μg/ml (for amonthly 300 mg regimen) 95% of the population are predicted to be in therange: 5-33 μg/ml (for a monthly 150 mg regimen) 11-70 μg/ml (for amonthly 300 mg regimen)

In addition, it has been determined that secukinumab has a T_(max) ofabout 7-8 days, and an elimination half-life of about 30 days. The PKinformation provided in this Example can be used to design differentdosing regimens for treatment of psoriasis at SoR, e.g., delivery of adifferent dosage of the IL-17 binding molecule (e.g., an IL-17 antibody,e.g., secukinumab) from the dosage used in the Examples or delivery ofthe same dosage as used in the Examples, but which is provided at adifferent time point from the time points used in the Examples. Bymaintaining the same PK profile, even though a dosing regimen maychange, a skilled artisan is expected to be able to use an IL-17 bindingmolecule (e.g., an IL-17 antibody, e.g., secukinumab) for treatment ofpsoriasis, including treatment of psoriasis at SoR.

1. A method of treating psoriasis, comprising subcutaneouslyadministering to a patient in need thereof a dose of about 150 mg-about300 mg of an IL-17 antibody weekly during week 0, 1, 2, 3, and 4, andthen bimonthly thereafter, wherein the IL-17 antibody comprises: i) animmunoglobulin variable heavy (V_(H)) domain comprising the amino acidsequence set forth as SEQ ID NO:8 and an immunoglobulin variable heavy(V_(L)) domain comprising the amino acid sequence set forth as SEQ IDNO:10; ii) an immunoglobulin V_(H) domain comprising the hypervariableregions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or iii) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.
 2. The method ofclaim 1, wherein the dose of the IL-17 antibody is about 150 mg or about300 mg.
 3. The method according to claim 2, wherein, prior to treatmentwith the IL-17 antibody, the patient has not been previously treatedwith a systemic agent for psoriasis.
 4. The method according to claim 2,wherein, prior to treatment with the IL-17 antibody, the patient hasbeen previously treated with a systemic agent for psoriasis.
 5. Themethod according to claim 4, wherein the systemic agent is selected fromthe group consisting of methotrexate, cyclosporine, fumaric acid esters,acitretin, alefacept, adalimumab, efalizumab, etanercept, infliximab,golimumab and ustekinumab.
 6. The method according to claim 5, whereinthe systemic agent is methotrexate.
 7. The method of claim 2, whereinthe dose of the IL-17 antibody is about 300 mg.
 8. The method of claim2, wherein the dose of the IL-17 antibody is about 150 mg.
 9. The methodof claim 2, wherein the patient has plaque psoriasis.
 10. The method ofclaim 9, wherein the patient has moderate to severe plaque psoriasis.11. The method of claim 2, wherein the patient has palm psoriasis, solepsoriasis, face psoriasis, scalp psoriasis, genital psoriasis, or nailpsoriasis.
 12. The method of claim 10, wherein the patient is an adultpatient.
 13. The method of claim 2, wherein the IL-17 antibody iscomprised in a pharmaceutical formulation, wherein said pharmaceuticalformulation further comprises a buffer and a stabilizer.
 14. The methodof claim 13, wherein the pharmaceutical formulation is in liquid form.15. The method of claim 13, wherein the pharmaceutical formulation is alyophilisate for reconstitution with an aqueous carrier prior toadministration to the patient.
 16. The method of claim 13, wherein thepharmaceutical formulation is contained within at least one pre-filledsyringe, at least one vial, at least one injection pen, or at least oneautoinjector.
 17. The method of claim 13, wherein the dose of the IL-17antibody is about 300 mg, wherein the pharmaceutical formulation iscontained within an autoinjector, wherein said autoinjector is containedwithin a kit, and wherein said kit further comprises instructions foruse.
 18. The method of claim 13, wherein the dose of the IL-17 antibodyis about 150 mg, wherein the pharmaceutical formulation is containedwithin a pre-filled syringe, an injection pen, or an autoinjector, whichis contained within a kit, and wherein said kit further comprisesinstructions for use.
 19. The method of claim 13, wherein the IL-17antibody is secukinumab.
 20. The method of claim 2, wherein the IL-17antibody has a T_(max) of about 7-8 days.
 21. The method of claim 2,wherein the IL-17 antibody has an absolute bioavailablilty of about60-about 80%.
 22. The method of claim 2, wherein the step ofadministering the IL-17 antibody every four weeks provides an averagesteady-state trough level of the IL-17 antibody between about 5μg/ml-about 70 μg/ml.
 23. The method of claim 22, wherein the step ofadministering the IL-17 antibody every four weeks provides an averagesteady-state trough level of the IL-17 antibody between about 5μg/ml-about 33 μg/ml.
 24. The method of claim 22, wherein the step ofadministering the IL-17 antibody every four weeks provides an averagesteady-state trough level of the IL-17 antibody between about 11μg/ml-about 70 μg/ml.
 25. The method of claim 2, wherein the IL-17antibody is a human monoclonal antibody.
 26. The method of claim 25,wherein the IL-17 antibody is of the IgG₁/kappa isotype.
 27. The methodaccording to claim 10, wherein, prior to treatment with the IL-17antibody, the patient has an Investigator Global Assessment (IGA) scoreof ≥3.
 28. The method of claim 2, wherein the dose of the IL-17 antibodyis about 300 mg and the patient weighs more than 90 kg.
 29. The methodof claim 2, wherein the dose of the IL-17 antibody is about 300 mg andthe patient weighs more than or equal to 90 kg.
 30. The method of claim2, wherein the dose of the IL-17 antibody is about 300 mg and thepatient weighs more than 100 kg.
 31. The method of claim 28, wherein theIL-17 antibody is secukinumab.
 32. The method of claim 29, wherein theIL-17 antibody is secukinumab.
 33. The method of claim 30, wherein theIL-17 antibody is secukinumab.
 34. The method of claim 2, wherein thedose of the IL-17 antibody is about 150 mg and the patient weighs lessthan 90 kg.
 35. The method of claim 2, wherein the dose of the IL-17antibody is about 150 mg and the patient weighs less than or equal to 90kg.
 36. The method of claim 2, wherein the dose of the IL-17 antibody isabout 150 mg and the patient weighs less than or equal to 100 kg.
 37. Amethod of treating psoriasis, comprising subcutaneously administering toa patient in need thereof a dose of about 150 mg or about 300 mgsecukinumab during week 0, 1, 2, 3, and 4, followed by a dose of about150 mg or about 300 mg secukinumab during a maintenance regimen, whereinthe maintenance regimen comprises administering secukinumab to thepatient every four weeks if the patient is a responder to treatment withsecukinumab or bimonthly if the patient is a partial responder or anon-responder to treatment with secukinumab.
 38. The method of claim 37,wherein the patient weighs more than or equal to 90 kg.
 39. A method oftreating psoriasis, comprising subcutaneously administering to a patientin need thereof a dose of about 150 mg or 300 mg secukinumab during week0, 1, 2, 3, and 4, and then bimonthly thereafter.
 40. The method ofclaim 39, wherein the patient weighs more than or equal to 90 kg.